research article impact of exposure to fenitrothion on vital...

Research ArticleImpact of Exposure to Fenitrothion on Vital Organs in Rats

Rasha Abdel-Ghany1 Ebaa Mohammed1 Shimaa Anis1 and Waleed Barakat12

1Department of Pharmacology amp Toxicology Faculty of Pharmacy Zagazig University Zagazig Egypt2Department of Pharmacology amp Toxicology Faculty of Pharmacy Tabuk University Tabuk Saudi Arabia

Correspondence should be addressed to Waleed Barakat waled055yahoocom

Received 29 August 2016 Revised 12 October 2016 Accepted 18 October 2016

Academic Editor Steven J Bursian

Copyright copy 2016 Rasha Abdel-Ghany et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

This study was designed to investigate the impact of oral administration of fenitrothion (10mgkg) on liver kidney brain andlung function in rats The effect was studied on days 7 14 21 28 and 42 Our results have shown deterioration in liver functionas evidenced by the elevation in serum ALT AST ALP and bilirubin and reduction in albumin and hepatic glycogen This wasassociated with a state of hyperglycemia and hyperlipidemia and increased prothrombin time while hemoglobin content wasreduced In addition the kidney function was reduced as indicated by the elevation in serum creatinine uric acid and BUNwhile the serum levels of magnesium potassium and sodium were reduced This study also showed an impairment in brainneurotransmitter (elevated 5-HT glutamate GABA and reduced dopamine and norepinephrine level) This was associated with areduction in the barrier capacity in brain and lung Fenitrothion also caused a decrease in cholinesterase activity in serum lungand brain activity associated with a state of oxidative stress in all tested organs and hyperammonemia These results support thehazards of pesticide use and shows the importance of minimizing pesticide use or discovering new safe pesticides

1 Introduction

Organophosphorus pesticides (OPs) are among the mostwidely used insecticides globally and they are readily availablecommercially for domestic and industrial purposes [1] Thewidespread use of OPs by public health and agriculturalprograms has led to severe environmental pollution [2 3] thatconstitutes a significant potential health hazard because of thepossibility of the acute or chronic poisoning of humans andanimals [4]

Fenitrothion is one of the most widely used organophos-phorus pesticides mainly used in agriculture for controllingchewing and sucking insects It is also used for the control offlies mosquitos and cockroaches in public health programsandor indoor use [5]

Organophosphates affect many vital organs chronic tox-icity with organophosphorus pesticides may cause extremeinjury in liver cells [6] Liver enzymes endogenous antiox-idant status and essential trace elements were found to beadversely affected after chronic OPs intoxication to rats [7]In addition hematological parameters such as hemoglobin

leucocyte count and coagulation of blood have been consid-ered as bioindicators of toxicities following chronic exposureto malathion [8] and pyrethroids [9 10]

Neuronal necrosis has been observed in multiple corticaland subcortical regions in experimental rats exposed to OPs[6] as soman [11 12] fenthion [13] and methamidophos [14]In addition symptoms of chronic OPs toxicity vary betweenheadache sweating Parkinsonrsquos alterations in memory andpsychiatric or neuropsychological dysfunction [15 16] Inaddition the key findings of OPs toxicity in respiratorysystem include shortness of breath and rapidly progressivebradypnea leading to apnea due to loss of central inspiratorydrive causing central failure of breathing [17] Chronic expo-sure to organophosphorus pesticides leads to kidney failure[18] It has also been reported that pesticides exposure wasassociated with kidney cancer [1]

The present study was designed to evaluate the conse-quences of oral fenitrothion administration for 42 consecu-tive days on liver function and its possible deleterious actionon brain lung and kidney in albino rats

Hindawi Publishing CorporationJournal of ToxicologyVolume 2016 Article ID 5609734 18 pageshttpdxdoiorg10115520165609734

2 Journal of Toxicology

2 Materials and Methods

Fenitrothion (Sumithion 50 500mgmL) was purchasedfrom Kafr Elzayat Co for Insecticide Ind (Kafr ElzayatEgypt) Fenitrothion emulsion was freshly diluted in distilledwater to 10mgmL and orally administered at a dose of1mLkg rat body weight which corresponds to 10mgkg Thedifference in administered volume among animals was notmore than 12 based on body weight differences The doseof fenitrothion was selected based on a previous study thatused fenitrothion at 10 and 20mgkg [19]

21 Animals Male albino rats weighing 160 plusmn 10 g wereobtained from National Research Center (Cairo Egypt) andwere housed in plastic cages and allowed free access to astandard diet and tap water The rats were housed at 23 plusmn2∘C 12 hr darklight cycle All experimental procedures wereapproved by the Ethical Committee for Animal Handlingat Zagazig University (ECAHZU) (number P7-3-2013 andnumber P8-3-2013)

Animals were randomly allocated into 6 groups (119899 = 10)treated daily with the following C (control group treatedwithoral distilledwater 1mLkg for 42 days) F1 (oral fenitrothion1mLkg for 7 days) F2 (oral fenitrothion 1mLkg for 14days) F3 (oral fenitrothion 1mLkg for 21 days) F4 (oralfenitrothion 1mLkg for 28 days) and F6 (oral fenitrothion1mLkg for 42 days)

At the end of the experiment after overnight fastingblood was collected from the retroorbital plexus and cen-trifuged at 3500 rpm for 15 minutes with or without hep-arin and serumplasma was collected and stored at minus20∘CAnimals were sacrificed by decapitation and liver braincortex lung and kidneywere excised for preparation of tissuehomogenates The cortex was chosen because the controlcenters of consciousness and memory are located mainly incerebral cortex [20]

22 Methods AChE activity in brain cortex and lung tis-sue was determined colorimetrically using acetylthiocholineiodide and 551015840-dithiobis (nitrobenzoate) (DTNB) at 412 nm[21] amino acids content was determined fluorometricallyusing ninhydrin at excitation of 377 nm and emission of451 nm for both glutamate and GABA [22 23] while contentof monoamines was determined fluorometrically using n-heptane at excitation at 320 nm and emission at 480 nm forDA excitation at 380 nm and emission at 480 nm for NE andexcitation at 355 nm and emission at 470 nm for 5-HT [23]Water content in brain and lung tissue was determined usingwet and dry weight method [24] Evans blue extravasation inbrain and lung tissue was determined colorimetrically usingEvans blue dye at 610 nm [24 25]

Liver glycogen content was determined by the gravimet-ric method using KoH trichloroacetic acid and absoluteethanol [26] and catalase (CAT) activity in tissue (liverbrain lung and kidney) was determined colorimetricallyusing potassium dichromate at 570 nm reduced glutathione(GSH) content in tissue (liver brain lung and kidney) wasdetermined colorimetrically using 551015840-dithiobis (nitroben-zoate) (DTNB) at 412 nm and malondialdehyde (MDA)

content in tissue (liver brain lung and kidney) was deter-mined colorimetrically using thiobarbituric acid (TBA) andtrichloroacetic acid at 535 nm [27ndash29]

The following parameters were assayed in serum usingkits supplied by Biodiagnostic Co (Cairo Egypt) ALTand AST [30] ALP [31] butyrylcholinesterase activity [32]total bilirubin [33] albumin [34] sodium [35] potassium[36] magnesium [37] cholesterol [38] HDL-cholesterol[39] LDL-cholesterol [40] blood urea nitrogen (BUN) [41]creatinine and uric acid contents [42]

Hemoglobin content [43] glucose level [44] and pro-thrombin time [45] were determined in blood using kitssupplied by Biodiagnostic Co (Cairo Egypt)

Liver serum brain lung and kidney total protein contentwere determined by colorimetric method using a kit suppliedby Biodiagnostic Co (Cairo Egypt) [46]

Liver serum and brain ammonia content were deter-mined by colorimetric method using a kit supplied byBiodiagnostic Co (Cairo Egypt) [47]

23 Statistical Analysis Data are expressed as means plusmn SDThe statistical significance of the data was determined usingone-way analysis of variance (ANOVA) followed by Tukeyrsquospost hoc test using SPSS software package version 10The levelof significance was taken as 119901 lt 005

3 Results

31 Effect on Some Liver Functions Administration of fen-itrothion for 7 14 21 28 and 42 days (F1 F2 F3 F4 andF6 resp) caused a significant gradual increase in serum ALTactivity compared with control group (48 496 521 563and 581 versus 413 ul) AST activity compared with controlgroup (962 1148 1269 1439 and 1519 versus 625 ul)ALP activity compared with control group (1378 1618 19942513 and 2503 versus 1121 ul) (Figure 1(a)) and serum totalbilirubin level compared with control group (056 09 and093 versus 032mgdL) (Figure 1(b))

On the other hand administration of fenitrothion for 714 21 28 and 42 days (F1 F2 F3 F4 and F6 resp) causeda significant gradual decrease in serum albumin comparedwith control group (411 373 359 317 and 31 versus489 gdL) (Figure 1(c)) and liver glycogen content comparedwith control group (306 264 216 and 21 versus 39 g100 gliver) (Figure 1(d))

32 Effects on Liver Histopathology Administration of fen-itrothion for 7 14 21 28 and 42 days (F1 F2 F3 F4and F6 resp) caused significant gradual deterioration inliver tissue starting by disorganized lobular patterns inhepatic parenchyma followed by congested hepatic tissueand programmed cell death (apoptosis) and focal necrosisand widening of the hepatic sinusoids beside cell swelling inthe remaining hepatic parenchyma and ending with inter-stitial lymphocytic aggregations and interlobular thickenededematous fibrous tissue (Figure 2)

33 Effect on Some Hematologic Parameters Administrationof fenitrothion for 14 21 28 and 42 days (F2 F3 F4 and F6

Journal of Toxicology 3

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Figure 1 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on some liver functions in rats Data areexpressed as mean plusmn SD119873 = 10 lowastSignificantly different from control group significantly different from fenitrothion at the previous timepoint at 119901 lt 005 using ANOVA followed by LSD and Tukeyrsquos post hoc test

resp) showed a significant gradual increase in blood glucoselevel compared with control group (10443 13741 15363 and16866 versus 8896mgdL) (Figure 3(a)) and prothrombintime compared with control group (1688 1712 1822 and1856 versus 1612 sec) (Figure 3(b))

This was accompanied by a significant decrease in bloodhemoglobin content (by 12 19 and 24 resp) comparedwithcontrol group starting from week 3 of fenitrothion adminis-tration (F3) that continued throughout the experiment (F4and F6) (Figure 3(c))

Administration of fenitrothion for 14 21 28 and 42 days(F2 F3 F4 and F6 resp) showed a state of hyperlipidemiaas evidenced by the significant gradual elevation in serumcholesterol compared with control group (5933 7249 9096and 9476 versus 5135mgdL) and LDL content comparedwith control group (169 228 297 3151 and 3567 versus1361mgdL) and the reduction in serumHDL comparedwith

control group (327 246 172 and 147 versus 406mgdL)compared with control group (Figure 3(d))

34 Effect on Kidney Function Administration of fenitroth-ion for 14 21 28 and 42 days (F2 F3 F4 and F6 resp) causeda significant gradual increase in serum creatinine contentcompared with control group (088 093 101 132 and 139versus 087mgdL) (Figure 4(a)) and uric acid (Figure 4(b))while serum blood urea nitrogen (BUN) content comparedwith control group (24 25 35 40 and 44 versus 24mgdL)was increased starting from F3 (Figure 4(c))

35 Effects on Kidney Histopathology Administration of fen-itrothion for 7 14 21 28 and 42 days (F1 F2 F3 F4 and F6resp) caused a gradual significant histopathological changesin kidney tissue starting fromminor changes in renal tubulesas well as glomeruli at the cortical portion and ending with


Figure 2 Effects of fenitrothion on liver histopathology in rats using H amp E staining (times400) C normal hepatic parenchyma F1 mildcongested disorganized hepatic lobules and slight cell swelling F2 moderate cell swelling associated with apoptosis and focal necrosis F3moderate degenerated and ballooned necrotic hepatocytes with lymphocytic aggregation and cell infiltration F4 severe disappearance ofhepatocytes and large areas of congestion lymphocytic aggregation and inflammation and F6 thickened interlobular tissue by edematousfibrous tissue and congested blood vessels N normal liver cells Black star congested cells with cytoplasmic vacuolation Green lightninglymphocytic aggregation Red arrow edematous fibrous tissue

severe degenerative changes in kidney tissue compared withcontrol group (Figure 5)

36 Effect on Electrolyte Administration of fenitrothion for7 14 21 28 and 42 days (F1 F2 F3 F4 and F6 resp) induceda significant gradual reduction in serum magnesium contentcompared with control group (093 083 07 064 and 045versus 11mmoll) potassium content compared with controlgroup (217 178 108 and 061 versus 262mmoll) andsodium content compared with control group (1054 906699 582 and 476 versus 1182mmoll) (Figures 6(a) 6(b)and 6(c))

37 Effect on Brain Neurotransmitters Administration offenitrothion for 14 21 28 and 42 days (F2 F3 F4 and F6resp) showed a significant gradual increase in brain 5-HTcontent compared with control group (42788 52789 62738and 75246 versus 35921 120583gg protein) glutamate contentcompared with control group (2337 329 4509 and 4646versus 2024120583molg protein) and GABA content in cortexcompared with control group (2018 2384 305 and 3535versus 1834 120583molg protein) (Figures 7(a) 7(b) and 7(c))

On the other hand administration of fenitrothion for 1421 28 and 42 days (F2 F3 F4 and F6 resp) was associatedwith a significant gradual reduction in brain DA contentcompared with control group (6999 5971 5009 and 4727versus 9172 120583gg protein) and NE content in brain cortexcompared with control group (16 1242 853 and 441 versus1834 120583gg protein) (Figures 7(d) and 7(e) resp)

38 Effect on Brain and Lung Barrier Integrity Adminis-tration of fenitrothion for 7 14 21 28 and 42 days (F1F2 F3 F4 and F6 resp) revealed a significant gradualdecrease in blood brain barrier integrity as evidenced bythe increase in Evans blue extravasation in brain comparedwith control group (137 1514 171 1906 and 2142 versus1291 120583gg protein) (Figure 8(a)) This was accompanied bya significant increase in brain water content compared withcontrol group (084 087 088 and 091 versus 079 g) startingfrom F2 (Figure 8(b))

Similarly administration of fenitrothion for 14 21 28and 42 days (F2 F3 F4 and F6 resp) revealed a significantgradual decrease in lung barrier integrity as evidenced bythe increase in Evans blue extravasation in lung compared


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Figure 3 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on some blood parameters in rats Data areexpressed as mean plusmn SD119873 = 10 lowastSignificantly different from control group significantly different from fenitrothion at the previous timepoint at 119901 lt 005 using ANOVA followed by Tukeyrsquos post hoc test

with control group (1831 1963 and 2144 versus 1719 120583ggprotein) (Figure 8(c)) which was also accompanied by asignificant increase in lung water content compared withcontrol group (086 09 and 091 versus 08 g) starting fromF2 (Figure 8(d))

39 Effects on Brain Histopathology Administration of fen-itrothion for 7 14 21 28 and 42 days (F1 F2 F3 F4and F6 resp) caused significant gradual deterioration inbrain tissue starting by focal scattered hemorrhagic areasLater on intense haemorrhage and narrow spaces with earlyencephalomalacia became visible in both lateral ventriclesThis was followed by demyelination of nerve axon in thewhite matter encephalomalacia cytotoxic edema neuronaldegeneration and intense microgliosis (Figure 9)

310 Effects on Lung Histopathology Administration of fen-itrothion for 7 14 21 28 and 42 days (F1 F2 F3 F4

and F6 resp) caused significant gradual deterioration inthe histopathology of lung tissue starting by focal hyper-trophied smooth muscles of the pulmonary blood vesselsand thickened intra-alveolar septa and ending with prevalenthypertrophied smoothmuscles interstitial hemorrhageswithnarrow alveolar spaces and intense thickened septa withperivascular leukocytic aggregation compared to controlgroup (Figure 10)

311 Effects on Cholinesterase Activity and Ammonia ContentAdministration of fenitrothion for 7 14 21 28 and 42 days(F1 F2 F3 F4 and F6 resp) caused a significant gradualdecrease in serum butyrylcholinesterase activity comparedwith control group (96963 855764 787932 754474 and696354 versus 16380 ul) lung acetylcholinesterase activitycompared with control group (27241 22803 17032 10428and 7616 versus 30249 120583molminmg protein) and brainacetylcholinesterase compared with control group (43968


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Figure 4 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on some kidney functions in rats Data areexpressed as mean plusmn SD119873 = 10 lowastSignificantly different from control group significantly different from fenitrothion at the previous timepoint at 119901 lt 005 using ANOVA followed by Tukeyrsquos post hoc test

39916 32457 20726 and 15576 versus 46493 120583molminmgprotein) (Figures 11(a) 11(b) and 11(c))

On the other hand fenitrothion caused a significantincrease in liver ammonia content compared with controlgroup (0073 01 0133 0183 and 0202 versus 0058 120583molgprotein) starting from the first week of administration (F1)and continuing throughout the experiment (F2 F3 F4 andF6) In addition fenitrothion caused a significant increasein ammonia content in serum compared with control group(0025 0036 0047 and 0065 versus 0022 120583moll) and brainammonia content comparedwith control group (0083 0093011 and 0124 versus 0072 120583molg protein) starting fromweek 2 of fenitrothion administration (F2) and continuingthroughout the experiment (F3 F4 and F6) as shown inFigure 11(d)

312 Effect on Oxidative Stress Biomarkers Administration offenitrothion caused a significant initial increase in catalase(CAT) activity after 7 days (F1) in liver brain kidney and lungcompared with control group (0085 versus 0069 037 versus034 006 versus 0053 and 018 versus 014 120583moleminmg

resp) However continued administration of fenitrothioncaused a gradual significant decrease in CAT activity in liverbrain kidney and lung after 21 28 and 42 days (F3 F4and F6 resp) compared with control group (006 0048and 0041 versus 0069 in liver 03 024 and 022 versus034 in brain 0048 0041 and 0034 versus 0053 in kidneyand 011 008 and 006 versus 014 120583moleminmg in lung)(Figure 12(a))

Similarly fenitrothion caused a significant initial increasein glutathione content (GSH) after 7 days (F1) in liver brainkidney and lung comparedwith control group (32 versus 28157 versus 134 202 versus 17 and 68 versus 59mgg resp)This was followed by a gradual significant decrease in GSHcontent in liver brain kidney and lung after 21 28 and 42days (F3 F4 and F6 resp) compared with control group (2724 and 198 versus 28 in liver 114 105 and 101 versus 134in brain 14 13 and 102 versus 17 in kidney and 484 385and 305 versus 592mgg in lung) (Figure 12(b))

On the other hand administration of fenitrothion for 7days (F1) caused a significant decrease in malondialdehyde(MDA) content in liver brain lung and kidney compared


Figure 5 Effects of fenitrothion on kidney histopathology in rats using HampE staining (times400) C normal segments of nephrons interstitiumand blood vessels F1 degenerative changes in glomeruli and tubules F2 partial necrosis of glomerular tafts and some renal tubular epitheliumin renal cortex F3 focal intense degenerative changes in renal tubules and few shrunken glomeruli F4 diffuse necrotic changes in renaltubules and glomeruli and F6 marked necrosis of tubular cells atrophy of the glomeruli and areas of interstitial infiltration of round cellsG renal glomeruli and T renal tubule

with control group (41 versus 52 25 versus 27 54 versus 57and 857 versus 1096 120583moleg resp) Continued administra-tion of fenitrothion caused a gradual significant decrease inMDA content in liver brain kidney and lung after 14 21 28and 42 days (F2 F3 F4 and F6 resp) compared with controlgroup (68 10 136 and 14 versus 52 in liver 41 51 57 and634 versus 27 in brain 704 88 113 and 1193 versus 57 inkidney and 1305 1799 218 and 2165 versus 1096 120583molegin lung) (Figure 12(c))

4 Discussion

This study was designed to investigate the effect of theorganophosphorus pesticide fenitrothion (10mgkgday pofor 6 weeks) on vital organs (liver blood kidney brain andlung) in albino rats

Concerning the effect of fenitrothion on hepatocellularintegrity this study showed significant gradual increase inALT and AST activity compared to control group startingfrom the first weekThese results coincidewith previous stud-ies that showed a significant increase in liver enzymes in ratsexposed to organophosphorus insecticides as fenitrothion[48]

The alteration in these enzymes might be attributed tohepatocellular damage and alteration in permeability of cellmembrane leading to leakage of these enzymes into bloodstream [49]

In the present study fenitrothion administration grad-ually increased ALP activity as compared to control groupThis result is in agreement with Kalender at al [1] whoreported that malathion treated rats had significantly higherALP activity than the control group This change may be inresponse to enhanced dephosphorylation of ALP for furthermetabolism of fenitrothion to be excreted with bile or due todefect in ALP excretion in bile by hepatocytes [50]

In the present study fenitrothion treated rats showedsignificant gradual increase in the level of bilirubin which isa normal metabolic product of hemoglobin in red blood cells[51] as previously shown by Jayusman et al [5] who reportedthat ingestion of pesticides caused a significant increase inbilirubin level

Additionally hyperbilirubinemia is toxic to the centralnervous system and may lead to a sequence of neurologicalsymptoms and signs termed bilirubin encephalopathy [52]

The present study showed a gradual decrease in albumincontent which coincides with [53] who showed reduction in


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Figure 6 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on serum electrolytes in rats Data areexpressed as mean plusmn SD119873 = 10 lowastSignificantly different from control group significantly different from fenitrothion at the previous timepoint at 119901 lt 005 using ANOVA followed by Tukeyrsquos post hoc test

albumin content after OPs exposure confirming the failurein liver functions [54] The reduction in albumin contentmay reflect increased albumin metabolism [55] or decreasedhepatic capacity to synthesize proteins due to increasednumber of injured hepatocytes [56]

The present study showed that fenitrothion adminis-tration caused deterioration in glucose homeostasis as evi-denced by significant gradual increase in blood glucose leveland a drop in hepatic glycogen content a previous studyhave reported that chronic exposure to OPs participates inhyperglycemia and depletion of glycogen content in liver andmuscle [57 58]

This might be attributed to disturbed glucose transportand glycogen metabolism [59] Additionally increased bloodglucose level may result from an imbalance between hepaticoutput of glucose and its peripheral uptake [60] or as aconsequence of abruptly increased catabolism tomeet higherOP induced energy demands [61]

In addition fenitrothion caused a significant gradualincrease in prothrombin time starting fromweek 2 Reference[53] showed alteration in coagulation after OPs exposure

confirming the failure in liver functions and decreasedhepatic capacity to synthesize coagulation factors [56]

The current study showed that exposure to fenitrothionwas accompanied by a significant gradual decrease in thelevel of hemoglobin from the first week which might explainthe state of hyperbilirubinemia since bilirubin is a normalmetabolic product of hemoglobin in red blood cells [51]These results are in accordance with those obtained by[62] who reported that OPs exposure altered hematologicalparameters in rats

The reduction in hemoglobin level might be attributed toimpairment of biosynthesis of heme in bone marrow [63] orbinding of OPs on iron followed by a lack of incorporationof iron in hemoglobin [64]

The current study has shown a gradual increase inserum cholesterol and LDL and gradual decrease in HDLafter administration of fenitrothion These results are inaccordance with those obtained by Kalender at al [1] Liveris involved in lipid synthesis metabolism and transportationand changes in plasma lipid level could serve as a simplemarker for assessing liver disorders [65] These alterations in


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Figure 7 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on some brain neurotransmitters inrats Data are expressed as mean plusmn SD 119873 = 10 lowastSignificantly different from control group significantly different from fenitrothion at theprevious time point at 119901 lt 005 using ANOVA followed by Tukeyrsquos post hoc test

lipid profilemight be attributed to the effect of fenitrothion onthe permeability of hepatocyte cell membrane or blockage ofthe bile duct which reduces or stops cholesterol secretion intothe duodenum [1] Also this could be attributed to increasedhepatic synthesis andor diminished hepatic degradation oflipids due to reduced lipoprotein lipase activity [66]

This study showed that fenitrothion caused a gradualelevation in BUN serum creatinine and serum uric acidstarting from third week indicating functional damage of thekidney These results coincide with previous studies whichdemonstrated that the kidney is one of the target organs ofOPs [67 68]


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Figure 8 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on barrier integrity in rats Data areexpressed as mean plusmn SD119873 = 10 lowastSignificantly different from control group significantly different from fenitrothion at the previous timepoint at 119901 lt 005 using ANOVA followed by Tukeyrsquos post hoc test

In this study fenitrothion caused a gradual decrease inserum Mg++ K+ and Na+ content The present findings areconsistent with [69] that reported that exposure to pesticidescaused decrease in serum Mg K and Na level The impor-tance of serum electrolytes is correlated with their involve-ment in many vital activities including muscle contrac-tion maintenance of acid-base balance and nerve impulseconduction [70]

Gumz et al [71] correlated these changes with alter-ation of the membrane configuration accompanied by cellmembrane damage and disorders in membrane permeabilityleading to alteration in electrolyte balance

Additionally Mossalam et al [72] showed that lipid per-oxidation products generated by pesticides can cause DNAdamage and directly inhibit protein synthesis including Na+K+ ATPase

Hypokalemia can exacerbate hepatic encephalopathy byincreasing renal ammoniagenesis and hence increasing sys-temic ammonia level [73] Furthermore Giuliani and Peri[74] reported that during hyponatremia excess water entersthe brain and the cells get swollen producing hyponatremicencephalopathy

In the present study fenitrothion caused a gradualincrease in brain glutamate GABA and serotonin (5-HT)content while the contents of norepinephrine and dopaminewere gradually decreased Rivera-Espinosa et al [75] havepreviously reported similar changes of brain neurotransmit-ters after liver injury Additionally Ahmed et al [76] have pre-viously reported similar changes of brain neurotransmittersafterOPs exposure Additionally exposures to pesticides havebeen reported to cause permanent alterations in GABAergicserotonergic [77] and dopaminergic systems [78]

The changes observed in GABAergic tone might be dueto modulation of central and peripheral benzodiazepinereceptors [79] while changes in glutamatergic dopaminergicand cholinergic system were attributed to disturbances in thesynthesis and degradation of amino acids by the liver [80] andamino acid efflux from andor reuptake by astrocytes [81]

In the present study a gradual increase in Evans blueextravasation in brain tissue and brain water content wasobserved following fenitrothion administration Like otherOPs fenitrothion can alter and cross the BBB leadingto neurological damage [82] With the alteration in BBBpermeability brain water and sodium content are increased


Figure 9 Effects of fenitrothion on brain histopathology in rats using H amp E staining (times400) C normal brain tissue F1 focal hemorrhagicareas in the cortex F2 scattered hemorrhage in brain ventricles and cytotoxic edema F3 focal hemorrhagic areas cytotoxic edemadegenerated neurons and focal microgliosis F4 cytotoxic edema and intense microgliosis and F6 degenerated neurons demyelinationof the white matter axons and encephalomalacia N normal brain cells Black star hemorrhagic area Green lightning cytotoxic edema Redarrow degenerated neurons and focal microgliosis Yellow head arrow demyelination of the white matter axons and encephalomalacia

causing brain edema as previously reported [82] In additionmetabolism of ammonia in astrocytes leads to glutamineaccumulation that may contribute to astrocyte swellingcytotoxic brain edema impaired astrocyteneuronal commu-nication and synaptic plasticity [83]

In a similar manner a gradual increase in EBE in lungtissue and lung water content was observed after fenitrothionadministration OPs can alter and cross the pleural mem-brane and cause lung injury through different mechanismsincluding ROS generation leading to pulmonary dysfunctionWith the increase in pleural permeability of pulmonarymicrovessels lung water content was increased profoundlycausing lung edema [84]

Additionally fluid accumulation causing brain and lungedema may also be due to the decreased production ofalbumin by the liver As albumin production diminishes fluidbegins to leak from vessels causing edema that can lead toalteration of mental status and increasing in breathing rateand effort [85]

Organophosphorus pesticides have been reported toinduce toxicity in mammals by inhibiting butyrylcholines-terase activity (BuChE) [86] and acetylcholinesterase(AChE) which leads to the accumulation of acetylcholineand the subsequent activation of cholinergic muscarinic andnicotinic receptors [87] leading to neuronal excitation and

then paralysis of cholinergic transmission [88] Thereforeacetylcholinesterase (AChE) and butyrylcholinesterase(BuChE) inhibition are a well-accepted index of organophos-phorus insecticides intoxication [89]

The present study has demonstrated a gradual decline inserumBuChE andbrain and lungAChE activity starting fromfirst week of fenitrothion administration Cholinesterasesinhibition may be due to direct effect of fenitrothion [90]or indirect effect of hyperammonemia andor decreasedsynthetic function of the liver as a result to hepatopathy [91]

Ammonia is normally converted to urea in the liver by aseries of enzymatic reactions [92] One important finding ofthis study was the gradual elevation in liver ammonia startingfrom the first week of fenitrothion administration while asignificant gradual increase in plasma and brain ammoniastarted from the second week

These results coincide with those reported by Scott et al[93] who showed a significant increase in plasma ammoniafollowing liver injury in rats and Penchalamma and Jacop[94] who reported the elevation in ammonia level in liverblood and kidney after OPs exposure

The elevated serum ammonia content can cross theblood brain barrier (BBB) [95] causing hepatic encephalopa-thy through several mechanisms including impaired brainenergy metabolism and autoregulation of blood flow [79]


Figure 10 Effects of fenitrothion on lung histopathology in rats using H amp E staining (times400) C normal lung tissue F1 slight hypertrophiedvascular smooth muscles F2 mild hypertrophied vascular smooth muscles F3 moderate hypertrophied vascular smooth muscles andthickened intra-alveolar septa F4 severe hypertrophied vascular smooth muscles and thickened intra-alveolar septa and F6 severehypertrophied vascular smooth muscles interstitial hemorrhages with narrow alveolar spaces and intense thickened septa with perivascularleukocytic aggregation N normal lung cells Black star hypertrophied vascular smooth muscles Green lightning thickening in the alveolarsepta Red arrow perivascular leukocytic aggregation

free radical production changes in lipid composition in braindue to alteration in lipid profile increased BBB permeabilityand brain edema [93]

In normal subjects intestinal ammonia produced fromnitrogen products is taken up by the liver and metabolizedto urea Liver disease whether acute or chronic is usuallyaccompanied by diminished hepatic urea synthesis deprivingthe body of its main route of ammonia detoxification [96]

Ammonia was shown to cause imbalance between exci-tatory and inhibitory neurotransmitters [79] Thereforeammonia content is widely used in the diagnosis of hepaticencephalopathy in cirrhotic patients with altered mentalstatus [97]

The current study has shown that administration offenitrothion resulted in an initial increase in antioxidantdefense mechanisms as evidenced by initial increase incatalase activity and glutathione content and an initialdecrease in malondialdehyde content in the first week whichwas reversed with continued administration of fenitrothionculminating in a state of oxidative stress in the liver brainlung and kidney

This indicates an initial attempt of the body to combatthe oxidative stress state induced by fenitrothion which failedand resulted in an evident state of oxidative stress in liverbrain and lung Organophosphorus pesticides have beenreported to cause oxidative stress and changes in antioxidantstatus system [98 99] Similar effects of OPs were previouslyreported by [1] in liver [100] in brain [101] in lung and [67]in kidney

Organophosphorus pesticide may induce oxidative stressthrough their ldquoredox-cyclingrdquo activity where they generatesuperoxide anions and hydrogen peroxide or through ROSgeneration via changes in normal antioxidant homeostasisthat results in depletion of antioxidants [102]

Organophosphorus pesticides have been shown to induceinflammation and cell infiltration [103]

In the present study the altered histopathological featuresof liver brain and lung were consistent with the biochemicalchanges and authenticated the injury caused by fenitrothionFenitrothion administration caused liver cell injury andcongestion of some hepatic cells (in 1st week) apoptosisfocal necrosis and hepatic cell swelling (in 2nd week)


Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025

Liver ammoniaSerum ammoniaBrain ammonia

lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)

Figure 11 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on cholinesterase activity and ammonialevel in rats Data are expressed as mean plusmn SD119873 = 10 lowastSignificantly different from control group significantly different from fenitrothionat the previous time point at 119901 lt 005 using ANOVA followed by Tukeyrsquos post hoc test

ballooned necrotic hepatocytes with lymphocytic aggrega-tion and cell infiltration (in 3rd week) large areas of con-gestion lymphocytic aggregation and inflammation (in 4thweek) interlobular tissue thickened by edematous fibroustissue and congested blood vessels (in 6th week) Thesechanges are in line with data recorded by [104 105]

Additionally marked histopathological alterations inbrain tissuewere observed following fenitrothion administra-tion including focal scattered hemorrhagic areas in cortex (in1st week) ischemic changes in brain neurons and cytotoxicedema (in 2nd week) cytotoxic edema degenerated neuronsand focal microgliosis (in 3rd week) cytotoxic edema andintense microgliosis (in 4th week) and finally degeneratedneurons demyelination of the white matter axons andencephalomalacia (in 6th week) Similar alterations werepreviously reported in chlorpyrifos (OPs) intoxicated animals[106]

Furthermore marked histopathological alterations wereobserved in the lung of fenitrothion treated groups includingslight hypertrophied vascular smooth muscles (in 1st week)mild hypertrophied vascular smooth muscles (in 2nd week)moderate hypertrophied vascular smoothmuscles and thick-ened intra-alveolar septa (in 3rd week) severe hypertrophiedvascular smooth muscles and thickened intra-alveolar septa(in 4th week) and severe hypertrophied vascular smoothmuscles interstitial hemorrhages with narrow alveolar spacesand intense thickened septa with perivascular leukocyticaggregation (in 6th week) These findings are supported byprevious studies [84 107]

5 Conclusion

In conclusion these results demonstrated that intoxicationwith fenitrothion induced significant damage of the liver


000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast

lowast lowast lowast lowastlowast

lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)

Figure 12 Effects of fenitrothion (10mgkg) for 1 2 3 4 and 6 weeks (F1 F2 F3 F4 and F6 resp) on antioxidant state in rats Data areexpressed as mean plusmn SD119873 = 10 lowastSignificantly different from control group Significantly different from fenitrothion at the previous timepoint at 119901 lt 005 using ANOVA followed by Tukeyrsquos post hoc test

brain lung and kidney leading to imbalance in liver brainlung and kidney functions Interestingly the liver was thefirst to be affected by fenitrothion administration whichmight imply a delayed effect of fenitrothion on the kidneybrain and lung due to pharmacokinetic influences or thatthe damaged liver has affected other organs through elevatedammonia bilirubin or defects in hepatic synthesis of vitalproteins as albumin and clotting factors

These results support the hazards of pesticide use andshows the importance of minimizing pesticide use or discov-ering new safe pesticides

Competing Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contributions

Ebaa Mohammed and Shimaa Anis equally contributed tothis work

Acknowledgments

This work was funded by the Academy for Scientific Researchand Technology Egypt (R112013-25052014) All experi-ments were performed at the Department of PharmacologyFaculty of Pharmacy Zagazig University Egypt

References

[1] S Kalender F G Uzun D Durak F Demir and Y KalenderldquoMalathion-induced hepatotoxicity in rats the effects of vita-mins C and Erdquo Food and Chemical Toxicology vol 48 no 2 pp633ndash638 2010

[2] MM LasramA BAnnabiN E Elj et al ldquoMetabolic disordersof acute exposure to malathion in adult Wistar ratsrdquo Journal ofHazardous Materials vol 163 no 2-3 pp 1052ndash1055 2009

[3] R Rekha S Raina and S Hamid ldquoHistopathological effects ofpesticide-cholopyrifos on kidney in albino ratsrdquo InternationalJournal of Research inMedical Sciences vol 1 no 4 p 465 2013


[4] A F Hernandez T Parron A M Tsatsakis M Requena RAlarcon and O Lopez-Guarnido ldquoToxic effects of pesticidemixtures at a molecular level their relevance to human healthrdquoToxicology vol 307 pp 136ndash145 2013

[5] P A Jayusman S B Budin A R Ghazali I S Taib and SR Louis ldquoEffects of palm oil tocotrienol-rich fraction on bio-chemical andmorphological alterations of liver in fenitrothion-treated ratsrdquoPakistan Journal of Pharmaceutical Sciences vol 27no 6 pp 1873ndash1880 2014

[6] S V KumarM Fareedullah Y Sudhakar B Venkateswarlu andEAKumar ldquoCurrent reviewonorganophosphorus poisoningrdquoArchives of Applied Science Research vol 2 no 4 pp 199ndash2152010

[7] S H Orabi B E Elbialy and S M Shawky ldquoAmeliorating andhypoglycemic effects of zinc against acute hepatotoxic effect ofchlorpyrifosrdquo Global Veterinaria vol 10 no 4 pp 439ndash4462013

[8] D Durak F G Uzun S Kalender A Ogutcu M Uzunhisar-cikli and Y Kalender ldquoMalathion-induced oxidative stress inhuman erythrocytes and the protective effect of vitamins C andE in vitrordquo Environmental Toxicology vol 24 no 3 pp 235ndash2422009

[9] T Vani N Saharan S D Roy et al ldquoAlteration in haemato-logical and biochemical parameters of Catla catla exposed tosub-lethal concentration of cypermethrinrdquo Fish Physiology andBiochemistry vol 38 no 6 pp 1577ndash1584 2012

[10] M A Al-Damegh ldquoToxicological impact of inhaled electricmosquito-repellent liquid on the rat a hematological cytokineindications oxidative stress and tumor markersrdquo InhalationToxicology vol 25 no 5 pp 292ndash297 2013

[11] J M Petras ldquoSoman neurotoxicityrdquo Fundamental and AppliedToxicology vol 1 no 2 p 242 1981

[12] T Kadar G Cohen R Sahar D Alkalai and S Shapira ldquoLong-term study of brain lesions following soman in comparison toDFP and metrazol poisoningrdquo Human and Experimental Toxi-cology vol 11 no 6 pp 517ndash523 1992

[13] B Veronesi K Jones and C Pope ldquoThe neurotoxicity ofsubchronic acetylcholinesterase (AChE) inhibition in rat hip-pocampusrdquo Toxicology and Applied Pharmacology vol 104 no3 pp 440ndash456 1990

[14] J R Pelegrino E E Calore P H N Saldiva V F Almeida NM Peres and L Vilela-de-Almeida ldquoMorphometric studies ofspecific brain regions of rats chronically intoxicated with theorganophosphate methamidophosrdquo Ecotoxicology and Environ-mental Safety vol 64 no 2 pp 251ndash255 2006

[15] T Dassanayake V Weerasinghe U Dangahadeniya et alldquoLong-term event-related potential changes following organo-phosphorus insecticide poisoningrdquo Clinical Neurophysiologyvol 119 no 1 pp 144ndash150 2008

[16] H E Speed C A Blaiss A Kim et al ldquoDelayed reductionof hippocampal synaptic transmission and spines followingexposure to repeated subclinical doses of organophosphoruspesticide in adult micerdquoToxicological Sciences vol 125 no 1 pp196ndash208 2012

[17] J L Carey C Dunn and R J Gaspari ldquoCentral respiratoryfailure during acute organophosphate poisoningrdquo RespiratoryPhysiology and Neurobiology vol 189 no 2 pp 403ndash410 2013

[18] A M Attia and H Nasr ldquoDimethoate-induced changes inbiochemical parameters of experimental rat serum and itsneutralization by black seed (Nigella sativa L) oilrdquo Slovak Jour-nal of Animal Science vol 2 pp 87ndash94 2009

[19] M E A Elhalwagy N S Darwish and EM Zaher ldquoProphylac-tic effect of green tea polyphenols against liver and kidney injuryinduced by fenitrothion insecticiderdquo Pesticide Biochemistry andPhysiology vol 91 no 2 pp 81ndash89 2008

[20] B J Baars S Franklin and T Z Ramsoslashy ldquoGlobal workspacedynamics cortical lsquobinding and propagationrsquo enables consciouscontentsrdquo Frontiers in Psychology vol 4 article 200 2013

[21] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[22] I P Lowe E Robins and G S Eyerman ldquoThe fluorometricmeasurement of glutamic decarboxylase and its distribution inbrainrdquo Journal of Neurochemistry vol 3 no 1 pp 8ndash18 1958

[23] M J G Harrison C D Marsden and P Jenner ldquoEffect ofexperimental ischemia onneurotransmitter amines in the gerbilbrainrdquo Stroke vol 10 no 2 pp 165ndash168 1979

[24] X Zhang H Li S Hu et al ldquoBrain edema after intracerebralhemorrhage in rats the role of inflammationrdquo Neurology Indiavol 54 no 4 pp 402ndash407 2006

[25] M Kaya R Kalayci M Kucuk et al ldquoEffect of losartan on theblood-brain barrier permeability in diabetic hypertensive ratsrdquoLife Sciences vol 73 no 25 pp 3235ndash3244 2003

[26] C A Good H M Kramer and M Somogyi ldquoThe determina-tion of glycogenrdquo The Journal of Biological Chemistry vol 100pp 485ndash491 1933

[27] E Beutler O Duron and BM Kelly ldquoImprovedmethod for thedetermination of blood glutathionerdquoThe Journal of Laboratoryand Clinical Medicine vol 61 pp 882ndash888 1963

[28] A K Sinha ldquoColorimetric assay of catalaserdquo Analytical Bio-chemistry vol 47 no 2 pp 389ndash394 1972

[29] T Yoshioka K Kawada T Shimada and M Mori ldquoLipidperoxidation in maternal and cord blood and protective mech-anism against activated-oxygen toxicity in the bloodrdquoAmericanJournal of Obstetrics amp Gynecology vol 135 no 3 pp 372ndash3761979

[30] S Reitman and S Frankel ldquoA colorimetricmethod for the deter-mination of serum glutamic oxalacetic and glutamic pyruvictransaminasesrdquo American Journal of Clinical Pathology vol 28no 1 pp 56ndash63 1957

[31] A Belfield andDMGoldberg ldquoRevised assay for serumphenylphosphatase activity using 4-amino-antipyrinerdquo Enzyme vol12 no 5 pp 561ndash573 1971

[32] M Knedel and R Bottger ldquoA kinetic method for determina-tion of the activity of pseudocholinesterase (acylcholine acyl-hydrolase 31 18)rdquo Klinische Wochenschrift vol 45 no 6 pp325ndash327 1967

[33] M I Walters and H W Gerarde ldquoAn ultramicromethod forthe determination of conjugated and total bilirubin in serum orplasmardquoMicrochemical Journal vol 15 no 2 pp 231ndash243 1970

[34] B T Doumas W A Watson and H G Biggs ldquoAlbumin stan-dards and the measurement of serum albumin with bromcresolgreenrdquo Clinica Chimica Acta vol 258 no 1 pp 21ndash30 1997

[35] P Trinder ldquoA rapid method for the determination of sodium inserumrdquoThe Analyst vol 76 no 907 pp 596ndash599 1951

[36] F W Sunderman Jr and F W Sunderman ldquoStudies in serumelectrolytes XXII A rapid reliable method for serum potas-sium using tetraphenylboronrdquo American Journal of ClinicalPathology vol 29 no 2 pp 95ndash103 1958


[37] E Gindler and D Heth Colorimetric Determination withBound Calmagite of Magnesium in Human Blood Serum Clin-ical Chemistry American Association for Clinical ChemistryWashington DC USA 1971

[38] W Richmond ldquoPreparation and properties of a cholesteroloxidase from Nocardia sp and its application to the enzymaticassay of total cholesterol in serumrdquo Clinical Chemistry vol 19no 12 pp 1350ndash1356 1973

[39] M Burstein H R Scholnick and RMorfin ldquoRapidmethod forthe isolation of lipoproteins fromhuman serumby precipitationwith polyanionsrdquo Journal of Lipid Research vol 11 no 6 pp583ndash595 1970

[40] H Wieland and D Seidel ldquoA simple specific method forprecipitation of low density lipoproteinsrdquo Journal of LipidResearch vol 24 no 7 pp 904ndash909 1983

[41] J K Fawcett and J E Scott ldquoA rapid and precise method for thedetermination of ureardquo Journal of Clinical Pathology vol 13 no2 pp 156ndash159 1960

[42] D Barham and P Trinder ldquoAn improved colour reagent for thedetermination of blood glucose by the oxidase systemrdquoAnalystvol 97 no 1151 pp 142ndash145 1972

[43] D L Drabkin and J H Austin ldquoSpectrophotometric studies ISpectrophotometric constants for commonhemoglobin deriva-tives in human dog and rabbit bloodrdquoThe Journal of BiologicalChemistry vol 98 no 2 pp 719ndash733 1932

[44] P Trinder ldquoDetermination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogenrdquo Jour-nal of Clinical Pathology vol 22 no 2 pp 158ndash161 1969

[45] RHull J Hirsh R Jay et al ldquoDifferent intensities of oral antico-agulant therapy in the treatment of proximal-vein thrombosisrdquoThe New England Journal of Medicine vol 307 no 27 pp 1676ndash1681 1982

[46] R Henry D Cannon and J Winkelman Clinical ChemistryPrinciples and Technics Harper amp Row Hagerstown Md USA1974

[47] K Konitzer and S Voigt ldquoDirect determination of ammoniumin blood and tissue extracts by means of the phenol by chloritereactionrdquoClinica Chimica Acta International Journal of ClinicalChemistry vol 8 article 5 1963

[48] J A Patil A J Patil and S P Govindwar ldquoBiochemical effects ofvarious pesticides on sprayers of grape gardensrdquo Indian Journalof Clinical Biochemistry vol 18 no 2 pp 16ndash22 2003

[49] B Kavitha S Shruthi S P Rai and Y Ramachandra ldquoPhyto-chemical analysis and hepatoprotective properties of Tinosporacordifolia against carbon tetrachloride-induced hepatic damagein ratsrdquo Journal of Basic and Clinical Pharmacy vol 2 no 3 pp139ndash142 2011

[50] N K Jain and A K Singhai ldquoProtective effects of Phyllanthusacidus (L) Skeels leaf extracts on acetaminophen and thioac-etamide induced hepatic injuries in Wistar ratsrdquo Asian PacificJournal of Tropical Medicine vol 4 no 6 pp 470ndash474 2011

[51] S W Oh E S Lee S Kim et al ldquoBilirubin attenuates the renaltubular injury by inhibition of oxidative stress and apoptosisrdquoBMC Nephrology vol 14 article 105 2013

[52] G Bortolussi E Codarin G Antoniali et al ldquoImpairment ofenzymatic antioxidant defenses is associated with bilirubin-induced neuronal cell death in the cerebellum ofUgt1 KOmicerdquoCell Death amp Disease vol 6 no 5 Article ID e1739 2015

[53] A-T H Mossa A A Refaie and A Ramadan ldquoEffect ofexposure to mixture of four organophosphate insecticides at noobserved adverse effect level dose on rat liver the protective role

of vitaminCrdquoResearch Journal of Environmental Toxicology vol5 no 6 pp 323ndash335 2011

[54] C Heneghan A Ward R Perera et al ldquoSelf-monitoring oforal anticoagulation systematic review and meta-analysis ofindividual patient datardquoThe Lancet vol 379 no 9813 pp 322ndash334 2012

[55] K A Amin and K S Hashem ldquoDeltamethrin-induced oxida-tive stress and biochemical changes in tissues and blood of cat-fish (Clarias gariepinus) antioxidant defense and role of alpha-tocopherolrdquo BMC Veterinary Research vol 8 article 45 2012

[56] M Anusha M Venkateswarlu V Prabhakaran S S Taj BP Kumari and D Ranganayakulu ldquoHepatoprotective activityof aqueous extract of Portulaca oleracea in combination withlycopene in ratsrdquo Indian Journal of Pharmacology vol 43 no 5pp 563ndash567 2011

[57] C I Acker and C W Nogueira ldquoChlorpyrifos acute exposureinduces hyperglycemia and hyperlipidemia in ratsrdquo Chemo-sphere vol 89 no 5 pp 602ndash608 2012

[58] R Nagaraju A K R Joshi and P S Rajini ldquoOrganophosphorusinsecticide monocrotophos possesses the propensity to induceinsulin resistance in rats on chronic exposurerdquo Journal of Dia-betes vol 7 no 1 pp 47ndash59 2015

[59] A D Southam A Lange A Hines et al ldquoMetabolomics revealstarget and off-target toxicities of a model organophosphatepesticide to roach (Rutilus rutilus) implications for biomoni-toringrdquo Environmental Science amp Technology vol 45 no 8 pp3759ndash3767 2011

[60] M Pakzad S Fouladdel A Nili-Ahmadabadi et al ldquoSublethalexposures of diazinon alters glucose homostasis in Wistar ratsbiochemical and molecular evidences of oxidative stress inadipose tissuesrdquo Pesticide Biochemistry and Physiology vol 105no 1 pp 57ndash61 2013

[61] A A Malekirad M Faghih M Mirabdollahi M Kiani AFathi and M Abdollahi ldquoNeurocognitive mental health andglucose disorders in farmers exposed to organophosphoruspesticidesrdquo Archives of Industrial Hygiene and Toxicology vol64 no 1 pp 1ndash8 2013

[62] S M Ismail ldquoProtective effects of vitamin C against biochemi-cal toxicity induced by malathion pesticides in male albino ratrdquoJournal of Evolutionary Biology Research vol 5 no 1 pp 1ndash52013

[63] B Mehra P Sharma U Kaushik and S Joshi ldquoEffect of fytolanon haematology and serum parameters of male albino ratsrdquoWorld Journal of Pharmaceutical Sciences vol 3 pp 817ndash8292014

[64] I A Hundekari A N Suryakar andD B Rathi ldquoAcute organo-phosphorus pesticide poisoning in North Karnataka Indiaoxidative damage haemoglobin level and total leukocyterdquoAfrican Health Sciences vol 13 no 1 pp 129ndash136 2013

[65] M Muthulingam P Mohandoss N Indra and S SethupathyldquoAntihepatotoxic efficacy of Indigofera tinctoria (Linn) onparacetamol induced liver damage in ratsrdquo International Journalof Pharmaceutical and Biomedical Research vol 1 no 1 pp 13ndash18 2010

[66] H A Hassan and M I Yousef ldquoAmeliorating effect of chicory(Cichorium intybus L)-supplemented diet against nitrosamineprecursors-induced liver injury and oxidative stress in maleratsrdquo Food and Chemical Toxicology vol 48 no 8-9 pp 2163ndash2169 2010

[67] S A Mansour and A-T H Mossa ldquoOxidative damage bio-chemical and histopathological alterations in rats exposed


to chlorpyrifos and the antioxidant role of zincrdquo PesticideBiochemistry and Physiology vol 96 no 1 pp 14ndash23 2010

[68] R R Elzoghby A F Hamoda A Abed-Ftah and M FaroukldquoProtective role of vitamin C and green tea extract onmalathion-induced hepatotoxicity and nephrotoxicity in ratsrdquoAmerican Journal of Pharmacology and Toxicology vol 9 no 3pp 177ndash188 2014

[69] V Sundaram V Manne and A M S Al-Osaimi ldquoAscites andspontaneous bacterial peritonitis recommendations from twoUnited States centersrdquo Saudi Journal of Gastroenterology vol 20no 5 pp 279ndash287 2014

[70] H R Pohl J S Wheeler and H E Murray ldquoSodium andpotassium in health and diseaserdquo in Interrelations betweenEssential Metal Ions and Human Diseases pp 29ndash47 SpringerBerlin Germany 2013

[71] M L Gumz L Rabinowitz and C S Wingo ldquoAn integratedview of potassium homeostasisrdquo The New England Journal ofMedicine vol 373 no 1 pp 60ndash72 2015

[72] HHMossalamOAAbd-ElAty ENMorgan S Youssaf andA M H Mackawy ldquoBiochemical and ultra structure studies ofthe antioxidant effect of aqueous extract of hibiscus sabdariffaon the nephrotoxicity induced by organophosphorous pesticide(malathion) on the adult albino ratsrdquo Journal of AmericanScience vol 7 no 12 pp 561ndash572 2011

[73] I D Weiner W E Mitch and J M Sands ldquoUrea and ammoniametabolism and the control of renal nitrogen excretionrdquo Clini-cal Journal of the American Society of Nephrology vol 10 no 8pp 1444ndash1458 2015

[74] C Giuliani and A Peri ldquoEffects of Hyponatremia on the BrainrdquoJournal of Clinical Medicine vol 3 no 4 pp 1163ndash1177 2014

[75] L Rivera-Espinosa E Floriano-Sanchez J Pedraza-Chaverrıet al ldquoContributions of microdialysis to new alternative ther-apeutics for hepatic encephalopathyrdquo International Journal ofMolecular Sciences vol 14 no 8 pp 16184ndash16206 2013

[76] M A E Ahmed H I Ahmed and E M El-Morsy ldquoMelatoninprotects against diazinon-induced neurobehavioral changes inratsrdquo Neurochemical Research vol 38 no 10 pp 2227ndash22362013

[77] D C Jones and G W Miller ldquoThe effects of environmentalneurotoxicants on the dopaminergic system a possible role indrug addictionrdquo Biochemical Pharmacology vol 76 no 5 pp569ndash581 2008

[78] J Zhang H Dai Y Deng et al ldquoNeonatal chlorpyrifos exposureinduces loss of dopaminergic neurons in young adult ratsrdquoToxicology vol 336 pp 17ndash25 2015

[79] H Cichoz-Lach and A Michalak ldquoCurrent pathogeneticaspects of hepatic encephalopathy and noncirrhotic hyperam-monemic encephalopathyrdquo World Journal of Gastroenterologyvol 19 no 1 pp 26ndash34 2013

[80] BMoghaddam andD Javitt ldquoFrom revolution to evolution theglutamate hypothesis of schizophrenia and its implication fortreatmentrdquo Neuropsychopharmacology vol 37 no 1 pp 4ndash152012

[81] M Sidoryk-Wegrzynowicz and M Aschner ldquoManganese toxi-city in the central nervous system the glutamineglutamate-120574-aminobutyric acid cyclerdquo Journal of Internal Medicine vol 273no 5 pp 466ndash477 2013

[82] Y AvrahamN C Grigoriadis T Poutahidis et al ldquoCannabidiolimproves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in micerdquo BritishJournal of Pharmacology vol 162 no 7 pp 1650ndash1658 2011

[83] D Haussinger and B Gorg ldquoInteraction of oxidative stressastrocyte swelling and cerebral ammonia toxicityrdquo CurrentOpinion in Clinical Nutrition and Metabolic Care vol 13 no 1pp 87ndash92 2010

[84] M A Noaishi M M Afify and A A Abd Allah ldquoStudy theinhalation exposure effect of pesticidesmixture in thewhite ratrdquoNature amp Science vol 11 no 7 pp 45ndash54 2013

[85] H Falcao and A M Japiassu ldquoAlbumin in critically ill patientscontroversies and recommendationsrdquo Revista Brasileira de Ter-apia Intensiva vol 23 no 1 pp 87ndash95 2011

[86] E Cataudella G Malaguarnera C Gagliano et al ldquoPesticidesexposure and the management of acute hepatic injuryrdquo ActaMedica Mediterranea vol 28 no 3 pp 245ndash252 2012

[87] J-M Collombet ldquoNerve agent intoxication recent neuropatho-physiological findings and subsequent impact onmedical man-agement prospectsrdquo Toxicology and Applied Pharmacology vol255 no 3 pp 229ndash241 2011

[88] A Osman S A Mastan S Rabia Banu and P Indira ldquoSub-lethal effect of cypermethrin on acetylcholinesterase (AChE)activity and acetylcholine (Ach) content in selected tissues ofChanna striatus (Bloch)rdquo Journal of Toxicology and Environ-mental Health Sciences vol 7 no 4 pp 31ndash37 2015

[89] M Pohanka ldquoInhibitors of acetylcholinesterase and butyryl-cholinesterase meet immunityrdquo International Journal of Molec-ular Sciences vol 15 no 6 pp 9809ndash9825 2014

[90] M E A Elhalwagy N S Darwish D A Shokry et al ldquoGarlicand 120572 lipoic supplementation enhance the immune system ofalbino rats and alleviate implications of pesticides mixturesrdquoInternational Journal of Clinical and ExperimentalMedicine vol8 no 5 pp 7689ndash7700 2015

[91] J L Franco T Posser J J Mattos et al ldquoZinc reversesmalathion-induced impairment in antioxidant defensesrdquo Tox-icology Letters vol 187 no 3 pp 137ndash143 2009

[92] F S Larsen J Gottstein and A T Blei ldquoCerebral hyperemiaand nitric oxide synthase in rats with ammonia-induced brainedemardquo Journal of Hepatology vol 34 no 4 pp 548ndash554 2001

[93] T R Scott V T Kronsten R D Hughes and D L ShawcrossldquoPathophysiology of cerebral oedema in acute liver failurerdquoWorld Journal of Gastroenterology vol 19 no 48 pp 9240ndash92552013

[94] R Penchalamma and D P Jacob ldquoDimethoate on proteinmetabolic profiles in rat kidneyrdquo Weekly Science ResearchJournal vol 2 no 11 pp 2321ndash7871 2014

[95] C R Bosoi X Yang J Huynh et al ldquoSystemic oxidative stressis implicated in the pathogenesis of brain edema in rats withchronic liver failurerdquo Free Radical Biology andMedicine vol 52no 7 pp 1228ndash1235 2012

[96] A Lemberg and M A Fernandez ldquoHepatic encephalopathyammonia glutamate glutamine and oxidative stressrdquo Annals ofHepatology vol 8 no 2 pp 95ndash102 2009

[97] J S Bajaj ldquoThe role of microbiota in hepatic encephalopathyrdquoGut Microbes vol 5 no 3 pp 397ndash403 2014

[98] T Rahman I Hosen M M T Islam and H U ShekharldquoOxidative stress and humanhealthrdquoAdvances in Bioscience andBiotechnology vol 3 no 7 pp 997ndash1019 2012

[99] Z Badade S Rastogi and S Singh ldquoAntioxidant status andoxidative stress in organophosphate pesticide poisoningrdquo Jour-nal of Dental and Medical Sciences vol 7 no 6 pp 20ndash24 2013

[100] A E-A A Diab E-S A A El-Aziz A A Hendawy M HZahra and R Z Hamza ldquoAntioxidant role of both propolis andginseng against neurotoxicity of chlorpyrifos and profenofos


in male ratsrdquo Life Science Journal-Acta Zhengzhou UniversityOverseas vol 9 pp 987ndash1008 2012

[101] M M Ahmed and N I Zaki ldquoAssessment the ameliorativeeffect of pomegranate and rutin on chlorpyrifos-ethyl-inducedoxidative stress in ratsrdquo Nature and Science vol 7 no 10 pp49ndash61 2009

[102] A M Al-Othman K S Al-Numair G E El-Desoky et alldquoProtection of 120572-tocopherol and selenium against acute effectsof malathion on liver and kidney of ratsrdquo African Journal ofPharmacy and Pharmacology vol 5 no 10 pp 1263ndash1271 2011

[103] M E A Elhalwagy and N I Zaki ldquoComparative study onpesticide mixture of organophosphorus and pyrethroid incommercial formulationrdquo Environmental Toxicology and Phar-macology vol 28 no 2 pp 219ndash224 2009

[104] T M Heikal M El-Sherbiny S A Hassan A Arafa and HZ Ghanem ldquoAntioxidant effect of selenium on hepatotoxicityinduced by chlorpyrifos in male ratsrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 4 no 4 pp 603ndash609 2012

[105] D L Baconi M Barca G Manda A-M Ciobanu and CBalalau ldquoInvestigation of the toxicity of some organophos-phorus pesticides in a repeated dose study in ratsrdquo RomanianJournal of Morphology and Embryology vol 54 no 2 pp 349ndash356 2013

[106] A Newairy and H Abdou ldquoEffect of propolis consumptionon hepatotoxicity and brain damage in male rats exposed tochlorpyrifosrdquo African Journal of Biotechnology vol 12 no 33pp 5232ndash5243 2013

[107] O Owoeye F V Edem B S Akinyoola S Rahaman E EAkang and G O Arinola ldquoHistological changes in liver andlungs of rats exposed to dichlorvos before and after vitaminsupplementationrdquo European Journal of Anatomy vol 16 no 3pp 190ndash198 2012

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


2 Materials and Methods

Fenitrothion (Sumithion 50 500mgmL) was purchasedfrom Kafr Elzayat Co for Insecticide Ind (Kafr ElzayatEgypt) Fenitrothion emulsion was freshly diluted in distilledwater to 10mgmL and orally administered at a dose of1mLkg rat body weight which corresponds to 10mgkg Thedifference in administered volume among animals was notmore than 12 based on body weight differences The doseof fenitrothion was selected based on a previous study thatused fenitrothion at 10 and 20mgkg [19]

21 Animals Male albino rats weighing 160 plusmn 10 g wereobtained from National Research Center (Cairo Egypt) andwere housed in plastic cages and allowed free access to astandard diet and tap water The rats were housed at 23 plusmn2∘C 12 hr darklight cycle All experimental procedures wereapproved by the Ethical Committee for Animal Handlingat Zagazig University (ECAHZU) (number P7-3-2013 andnumber P8-3-2013)

Animals were randomly allocated into 6 groups (119899 = 10)treated daily with the following C (control group treatedwithoral distilledwater 1mLkg for 42 days) F1 (oral fenitrothion1mLkg for 7 days) F2 (oral fenitrothion 1mLkg for 14days) F3 (oral fenitrothion 1mLkg for 21 days) F4 (oralfenitrothion 1mLkg for 28 days) and F6 (oral fenitrothion1mLkg for 42 days)

At the end of the experiment after overnight fastingblood was collected from the retroorbital plexus and cen-trifuged at 3500 rpm for 15 minutes with or without hep-arin and serumplasma was collected and stored at minus20∘CAnimals were sacrificed by decapitation and liver braincortex lung and kidneywere excised for preparation of tissuehomogenates The cortex was chosen because the controlcenters of consciousness and memory are located mainly incerebral cortex [20]

22 Methods AChE activity in brain cortex and lung tis-sue was determined colorimetrically using acetylthiocholineiodide and 551015840-dithiobis (nitrobenzoate) (DTNB) at 412 nm[21] amino acids content was determined fluorometricallyusing ninhydrin at excitation of 377 nm and emission of451 nm for both glutamate and GABA [22 23] while contentof monoamines was determined fluorometrically using n-heptane at excitation at 320 nm and emission at 480 nm forDA excitation at 380 nm and emission at 480 nm for NE andexcitation at 355 nm and emission at 470 nm for 5-HT [23]Water content in brain and lung tissue was determined usingwet and dry weight method [24] Evans blue extravasation inbrain and lung tissue was determined colorimetrically usingEvans blue dye at 610 nm [24 25]

Liver glycogen content was determined by the gravimet-ric method using KoH trichloroacetic acid and absoluteethanol [26] and catalase (CAT) activity in tissue (liverbrain lung and kidney) was determined colorimetricallyusing potassium dichromate at 570 nm reduced glutathione(GSH) content in tissue (liver brain lung and kidney) wasdetermined colorimetrically using 551015840-dithiobis (nitroben-zoate) (DTNB) at 412 nm and malondialdehyde (MDA)

content in tissue (liver brain lung and kidney) was deter-mined colorimetrically using thiobarbituric acid (TBA) andtrichloroacetic acid at 535 nm [27ndash29]

The following parameters were assayed in serum usingkits supplied by Biodiagnostic Co (Cairo Egypt) ALTand AST [30] ALP [31] butyrylcholinesterase activity [32]total bilirubin [33] albumin [34] sodium [35] potassium[36] magnesium [37] cholesterol [38] HDL-cholesterol[39] LDL-cholesterol [40] blood urea nitrogen (BUN) [41]creatinine and uric acid contents [42]

Hemoglobin content [43] glucose level [44] and pro-thrombin time [45] were determined in blood using kitssupplied by Biodiagnostic Co (Cairo Egypt)

Liver serum brain lung and kidney total protein contentwere determined by colorimetric method using a kit suppliedby Biodiagnostic Co (Cairo Egypt) [46]

Liver serum and brain ammonia content were deter-mined by colorimetric method using a kit supplied byBiodiagnostic Co (Cairo Egypt) [47]

23 Statistical Analysis Data are expressed as means plusmn SDThe statistical significance of the data was determined usingone-way analysis of variance (ANOVA) followed by Tukeyrsquospost hoc test using SPSS software package version 10The levelof significance was taken as 119901 lt 005

3 Results

31 Effect on Some Liver Functions Administration of fen-itrothion for 7 14 21 28 and 42 days (F1 F2 F3 F4 andF6 resp) caused a significant gradual increase in serum ALTactivity compared with control group (48 496 521 563and 581 versus 413 ul) AST activity compared with controlgroup (962 1148 1269 1439 and 1519 versus 625 ul)ALP activity compared with control group (1378 1618 19942513 and 2503 versus 1121 ul) (Figure 1(a)) and serum totalbilirubin level compared with control group (056 09 and093 versus 032mgdL) (Figure 1(b))

On the other hand administration of fenitrothion for 714 21 28 and 42 days (F1 F2 F3 F4 and F6 resp) causeda significant gradual decrease in serum albumin comparedwith control group (411 373 359 317 and 31 versus489 gdL) (Figure 1(c)) and liver glycogen content comparedwith control group (306 264 216 and 21 versus 39 g100 gliver) (Figure 1(d))

32 Effects on Liver Histopathology Administration of fen-itrothion for 7 14 21 28 and 42 days (F1 F2 F3 F4and F6 resp) caused significant gradual deterioration inliver tissue starting by disorganized lobular patterns inhepatic parenchyma followed by congested hepatic tissueand programmed cell death (apoptosis) and focal necrosisand widening of the hepatic sinusoids beside cell swelling inthe remaining hepatic parenchyma and ending with inter-stitial lymphocytic aggregations and interlobular thickenededematous fibrous tissue (Figure 2)

33 Effect on Some Hematologic Parameters Administrationof fenitrothion for 14 21 28 and 42 days (F2 F3 F4 and F6


Seru

m le

vel (

UL

)

0

50

100

150

200

250

300

ALTASTALP


lowastlowast

lowast lowastlowast

lowast

lowast

lowast


lowast

lowast

lowast

(a)

Seru

m to

tal b

iliru

bin

(mg

dL)

02

03

04

05

06

07

08

09

10

lowast

lowast

lowast lowast


(b)

Seru

m al

bum

in (g

md

L)

283032343638404244464850

lowast

lowastlowast


lowast

(c)

Hep

atic

gly

coge

n (m

gg

liver

)

15

20

25

30

35

40

45

lowast

lowast

lowast


















Bloo

d gl

ucos

e (m

gdL

)

80

100

120

140

160

180

lowast

lowast

lowast

lowast


Prot

hrom

bin

time (

sec)

155

160

165

170

175

180

185

190

lowast

lowast


lowast

lowast

(b)

Bloo

d he

mog

lobi

n (g

d)

10

11

12

13

14

15

lowast

lowast

lowast


(c)

Seru

m le

vel (

mg

dL)

0

20

40

60

80

100

120

CholesterolLDLHDL

lowast

lowast

lowast lowast




lowast

(d)








Seru

m cr

eatin

ine (

mg

dL)

08

09

10

11

12

13

14

15

lowast

lowast

lowast

lowast


Seru

m u

ric ac

id (m

gdL

)

03

04

05

06

07

08

lowast

lowast

lowast

lowast


Seru

m B

UN

(mg

dL)

20

25

30

35

40

45

50

lowast

lowast

lowast












4 Discussion









Seru

m M

g (m

mol

eL)

04

05

06

07

08

09

10

11

12

lowast

lowastlowast

lowast


lowast

(a)

Seru

m K

(mm

ole

L)

00

05

10

15

20

25

30

lowast

lowast

lowast

lowast


Seru

m N

a (m

mol

eL)

40

60

80

100

120

140

lowast

lowast

lowast

lowast


lowast

(c)











300

400

500

600

700

800

lowast

lowast

lowast

lowastBr

ain5

-HT

(120583g

g pr

otei

n)


15

20

25

30

35

40

45

50

lowast

lowast

lowast

Brai

n gl

utam

ate (

120583m

ole

g pr

otei

n)


161820222426283032343638

lowast

lowast

lowast

lowast

Brai

n G

ABA

(120583m

ole

g pr

otei

n)


40

50

60

70

80

90

100

lowast

lowast

lowastlowast

Brai

n D

A (120583

gg

prot

ein)


2

4

6

8

10

12

14

16

18

20

lowast

lowast

lowast

lowast

Brai

n N

E (120583

gg

prot

ein)






12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Seru

m le

vel (

UL

)

0

50

100

150

200

250

300

ALTASTALP


lowastlowast

lowast lowastlowast

lowast

lowast

lowast


lowast

lowast

lowast

(a)

Seru

m to

tal b

iliru

bin

(mg

dL)

02

03

04

05

06

07

08

09

10

lowast

lowast

lowast lowast


(b)

Seru

m al

bum

in (g

md

L)

283032343638404244464850

lowast

lowastlowast


lowast

(c)

Hep

atic

gly

coge

n (m

gg

liver

)

15

20

25

30

35

40

45

lowast

lowast

lowast


















Bloo

d gl

ucos

e (m

gdL

)

80

100

120

140

160

180

lowast

lowast

lowast

lowast


Prot

hrom

bin

time (

sec)

155

160

165

170

175

180

185

190

lowast

lowast


lowast

lowast

(b)

Bloo

d he

mog

lobi

n (g

d)

10

11

12

13

14

15

lowast

lowast

lowast


(c)

Seru

m le

vel (

mg

dL)

0

20

40

60

80

100

120

CholesterolLDLHDL

lowast

lowast

lowast lowast




lowast

(d)








Seru

m cr

eatin

ine (

mg

dL)

08

09

10

11

12

13

14

15

lowast

lowast

lowast

lowast


Seru

m u

ric ac

id (m

gdL

)

03

04

05

06

07

08

lowast

lowast

lowast

lowast


Seru

m B

UN

(mg

dL)

20

25

30

35

40

45

50

lowast

lowast

lowast












4 Discussion









Seru

m M

g (m

mol

eL)

04

05

06

07

08

09

10

11

12

lowast

lowastlowast

lowast


lowast

(a)

Seru

m K

(mm

ole

L)

00

05

10

15

20

25

30

lowast

lowast

lowast

lowast


Seru

m N

a (m

mol

eL)

40

60

80

100

120

140

lowast

lowast

lowast

lowast


lowast

(c)











300

400

500

600

700

800

lowast

lowast

lowast

lowastBr

ain5

-HT

(120583g

g pr

otei

n)


15

20

25

30

35

40

45

50

lowast

lowast

lowast

Brai

n gl

utam

ate (

120583m

ole

g pr

otei

n)


161820222426283032343638

lowast

lowast

lowast

lowast

Brai

n G

ABA

(120583m

ole

g pr

otei

n)


40

50

60

70

80

90

100

lowast

lowast

lowastlowast

Brai

n D

A (120583

gg

prot

ein)


2

4

6

8

10

12

14

16

18

20

lowast

lowast

lowast

lowast

Brai

n N

E (120583

gg

prot

ein)






12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of










Bloo

d gl

ucos

e (m

gdL

)

80

100

120

140

160

180

lowast

lowast

lowast

lowast


Prot

hrom

bin

time (

sec)

155

160

165

170

175

180

185

190

lowast

lowast


lowast

lowast

(b)

Bloo

d he

mog

lobi

n (g

d)

10

11

12

13

14

15

lowast

lowast

lowast


(c)

Seru

m le

vel (

mg

dL)

0

20

40

60

80

100

120

CholesterolLDLHDL

lowast

lowast

lowast lowast




lowast

(d)








Seru

m cr

eatin

ine (

mg

dL)

08

09

10

11

12

13

14

15

lowast

lowast

lowast

lowast


Seru

m u

ric ac

id (m

gdL

)

03

04

05

06

07

08

lowast

lowast

lowast

lowast


Seru

m B

UN

(mg

dL)

20

25

30

35

40

45

50

lowast

lowast

lowast












4 Discussion









Seru

m M

g (m

mol

eL)

04

05

06

07

08

09

10

11

12

lowast

lowastlowast

lowast


lowast

(a)

Seru

m K

(mm

ole

L)

00

05

10

15

20

25

30

lowast

lowast

lowast

lowast


Seru

m N

a (m

mol

eL)

40

60

80

100

120

140

lowast

lowast

lowast

lowast


lowast

(c)











300

400

500

600

700

800

lowast

lowast

lowast

lowastBr

ain5

-HT

(120583g

g pr

otei

n)


15

20

25

30

35

40

45

50

lowast

lowast

lowast

Brai

n gl

utam

ate (

120583m

ole

g pr

otei

n)


161820222426283032343638

lowast

lowast

lowast

lowast

Brai

n G

ABA

(120583m

ole

g pr

otei

n)


40

50

60

70

80

90

100

lowast

lowast

lowastlowast

Brai

n D

A (120583

gg

prot

ein)


2

4

6

8

10

12

14

16

18

20

lowast

lowast

lowast

lowast

Brai

n N

E (120583

gg

prot

ein)






12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Seru

m cr

eatin

ine (

mg

dL)

08

09

10

11

12

13

14

15

lowast

lowast

lowast

lowast


Seru

m u

ric ac

id (m

gdL

)

03

04

05

06

07

08

lowast

lowast

lowast

lowast


Seru

m B

UN

(mg

dL)

20

25

30

35

40

45

50

lowast

lowast

lowast












4 Discussion









Seru

m M

g (m

mol

eL)

04

05

06

07

08

09

10

11

12

lowast

lowastlowast

lowast


lowast

(a)

Seru

m K

(mm

ole

L)

00

05

10

15

20

25

30

lowast

lowast

lowast

lowast


Seru

m N

a (m

mol

eL)

40

60

80

100

120

140

lowast

lowast

lowast

lowast


lowast

(c)











300

400

500

600

700

800

lowast

lowast

lowast

lowastBr

ain5

-HT

(120583g

g pr

otei

n)


15

20

25

30

35

40

45

50

lowast

lowast

lowast

Brai

n gl

utam

ate (

120583m

ole

g pr

otei

n)


161820222426283032343638

lowast

lowast

lowast

lowast

Brai

n G

ABA

(120583m

ole

g pr

otei

n)


40

50

60

70

80

90

100

lowast

lowast

lowastlowast

Brai

n D

A (120583

gg

prot

ein)


2

4

6

8

10

12

14

16

18

20

lowast

lowast

lowast

lowast

Brai

n N

E (120583

gg

prot

ein)






12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




4 Discussion









Seru

m M

g (m

mol

eL)

04

05

06

07

08

09

10

11

12

lowast

lowastlowast

lowast


lowast

(a)

Seru

m K

(mm

ole

L)

00

05

10

15

20

25

30

lowast

lowast

lowast

lowast


Seru

m N

a (m

mol

eL)

40

60

80

100

120

140

lowast

lowast

lowast

lowast


lowast

(c)











300

400

500

600

700

800

lowast

lowast

lowast

lowastBr

ain5

-HT

(120583g

g pr

otei

n)


15

20

25

30

35

40

45

50

lowast

lowast

lowast

Brai

n gl

utam

ate (

120583m

ole

g pr

otei

n)


161820222426283032343638

lowast

lowast

lowast

lowast

Brai

n G

ABA

(120583m

ole

g pr

otei

n)


40

50

60

70

80

90

100

lowast

lowast

lowastlowast

Brai

n D

A (120583

gg

prot

ein)


2

4

6

8

10

12

14

16

18

20

lowast

lowast

lowast

lowast

Brai

n N

E (120583

gg

prot

ein)






12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Seru

m M

g (m

mol

eL)

04

05

06

07

08

09

10

11

12

lowast

lowastlowast

lowast


lowast

(a)

Seru

m K

(mm

ole

L)

00

05

10

15

20

25

30

lowast

lowast

lowast

lowast


Seru

m N

a (m

mol

eL)

40

60

80

100

120

140

lowast

lowast

lowast

lowast


lowast

(c)











300

400

500

600

700

800

lowast

lowast

lowast

lowastBr

ain5

-HT

(120583g

g pr

otei

n)


15

20

25

30

35

40

45

50

lowast

lowast

lowast

Brai

n gl

utam

ate (

120583m

ole

g pr

otei

n)


161820222426283032343638

lowast

lowast

lowast

lowast

Brai

n G

ABA

(120583m

ole

g pr

otei

n)


40

50

60

70

80

90

100

lowast

lowast

lowastlowast

Brai

n D

A (120583

gg

prot

ein)


2

4

6

8

10

12

14

16

18

20

lowast

lowast

lowast

lowast

Brai

n N

E (120583

gg

prot

ein)






12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


300

400

500

600

700

800

lowast

lowast

lowast

lowastBr

ain5

-HT

(120583g

g pr

otei

n)


15

20

25

30

35

40

45

50

lowast

lowast

lowast

Brai

n gl

utam

ate (

120583m

ole

g pr

otei

n)


161820222426283032343638

lowast

lowast

lowast

lowast

Brai

n G

ABA

(120583m

ole

g pr

otei

n)


40

50

60

70

80

90

100

lowast

lowast

lowastlowast

Brai

n D

A (120583

gg

prot

ein)


2

4

6

8

10

12

14

16

18

20

lowast

lowast

lowast

lowast

Brai

n N

E (120583

gg

prot

ein)






12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


12

14

16

18

20

22

24

lowast

lowast

lowast

lowast

Brai

n Ev

ans b

lue (

120583g

g pr

otei

n)


lowast

(a)

Brai

n ed

ema (

)

076

078

080

082

084

086

088

090

092

lowast

lowast

lowast


16

17

18

19

20

21

22

23

lowastlowast

lowast

lowast

Lung

Eva

ns b

lue (

120583g

g pr

otei

n)


Lung

edem

a (

)

076

078

080

082

084

086

088

090

092

094

lowast

lowast

lowast
































Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of























Seru

m B

uChE

(UL

)

6000

8000

10000

12000

14000

16000

18000

lowast

lowastlowast

lowastlowast


50

100

150

200

250

300

350

lowast

lowast

lowast

lowastlowastLu

ng A

ChE

(120583m

ole

min

mg

prot

ein)


100

150

200

250

300

350

400

450

500

lowast

lowast

lowast

lowast

Brai

n AC

hE (120583

mol

em

inm

g pr

otei

n)


lowast

(c)

000

005

010

015

020

025


lowast

lowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

lowastlowast

Am

mon

ia (120583

mol

eg

prot

ein)


lowast

(d)





5 Conclusion



000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


000

005

010

015

020

025

030

035

040

LiverBrain

KidneyLung

lowastlowast

lowast

lowast

lowastlowast

lowast lowast

lowast

lowastlowast

CAT

activ

ity (120583

mol

em

inm

g pr

otei

n)


lowast

lowast

lowast

lowastlowast

(a)

GSH

leve

l (m

gg

prot

ein)

0

1

2

3

4

5

6

7

8

lowastlowast

lowast



lowastlowast

lowastlowast


LiverBrain

KidneyLung

lowast

lowast

lowast

lowast

(b)

0

5

10

15

20

25

lowastlowast

lowast lowast


lowast

lowastlowast

lowast

lowast

MD

A le

vel (120583

mol

eg

prot

ein)


LiverBrain

KidneyLung

lowast

lowast

lowastlowast

lowast

lowast

(c)




Competing Interests




Acknowledgments


References























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




















































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

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