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Ferulic Acid, a Natural Phenolic Antioxidant Modulates Altered LipidProfiles During Alcohol and Thermally Oxidized Sunflower Oil InducedToxicityRajagopalan Rukkumani a; Kode Aruna a; Penumathsa Suresh Varma b;Venugopal PadmanabhanMenon c

a Department of Biochemistry, b Centre for Micronutrient Research, Annamalai University, c

Department of Biochemistry, Annamalai University,

To cite this Article Rukkumani, Rajagopalan , Aruna, Kode , Varma, Penumathsa Suresh andMenon, VenugopalPadmanabhan(2005) 'Ferulic Acid, a Natural Phenolic Antioxidant Modulates Altered Lipid Profiles During Alcohol andThermally Oxidized Sunflower Oil Induced Toxicity', Journal of Nutraceuticals, Functional & Medical Foods, 4: 3, 119 —132To link to this Article: DOI: 10.1300/J133v04n03_08URL: http://dx.doi.org/10.1300/J133v04n03_08

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Ferulic Acid,a Natural Phenolic Antioxidant

Modulates Altered Lipid ProfilesDuring Alcohol and Thermally Oxidized

Sunflower Oil Induced Toxicity

Rajagopalan RukkumaniKode Aruna

Penumathsa Suresh VarmaVenugopal Padmanabhan Menon

ABSTRACT. Ethanol is a powerful inducer of hyperlipidemia in bothanimals and humans. Lipid abnormalities seen after ethanol consump-tion include alterations in the levels of free cholesterol, cholesteryl es-ters, fatty acids, phospholipids and triacylglycerol. Intake of high fat dietalong with ethanol primes the hyperlipidemic effects of ethanol. Alcoholinduced disturbances in lipid pattern were found to be exacerbated when

Rajagopalan Rukkumani, MSc, MPhil, and Kode Aruna, MSc, MPhil, are PhDResearch Scholars, Department of Biochemistry, Penumathsa Suresh Varma, MSc,MPhil, is Research Scientist, Centre for Micronutrient Research, Annamalai University.

Dr. Venugopal Padmanabhan Menon is Professor and Head, Department of Bio-chemistry, Annamalai University, and the Chairman, Centre for Micronutrient Research.He is doing extensive research on the free radical induced diseases and their preventionby natural products and analogs.

Address correspondence to: Dr. Venugopal Padmanabhan Menon, Professor andHead, Department of Biochemistry, Annamalai University, Annamalainagar-608 002,Tamil Nadu, India (E-mail: [email protected]).

Financial support rendered by Jawaharlal Nehru Memorial Fund, New Delhi, India,for the above study is gratefully acknowledged.

This article received editorial review by The Haworth Press.

Journal of Nutraceuticals, Functional & Medical Foods, Vol. 4(3/4) 2004http://www.haworthpress.com/web/JNFMF

2004 by The Haworth Press, Inc. All rights reserved.Digital Object Identifier: 10.1300/J133v04n03_08 119

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the fat is thermally oxidized. In the present communication, we have in-vestigated the influence of ferulic acid, a naturally occurring nutritionalcomponent on alcohol and thermally oxidized sunflower oil (∆ PUFA)induced hyperlipidemia. To evaluate the antihyperlipidemic potential offerulic acid (FA), we analyzed the variation in lipid profiles cholesterol,triglycerides (TG), phospholipids (PL) and free fatty acids (FFA) inplasma, liver, heart and kidney. The results showed that there was a sig-nificant elevation in the levels of cholesterol, TG and FFA in alcohol, ∆PUFA, alcohol + ∆ PUFA administered rats, which was effectively abro-gated by FA treatment. In contrast, the phospholipids were significantlydecreased in liver and kidney, but increased in plasma and heart duringalcohol, ∆ PUFA and alcohol + ∆ PUFA ingestion, which were posi-tively modulated by FA. Inspite of lipid accumulation, the gain in bodyweight was less in alcohol, ∆ PUFA and alcohol + ∆ PUFA groups com-pared to control rats. FA treated groups showed a significant improve-ment in the weight. Thus from the results obtained, we conclude that FAeffectively protects the system against alcohol and ∆ PUFA induced tox-icity and can be developed as a potent drug for the treatment ofhyperlipidemia. [Article copies available for a fee from The Haworth Docu-ment Delivery Service: 1-800-HAWORTH. E-mail address: <[email protected]> Website: <http://www.HaworthPress.com> 2004 by TheHaworth Press, Inc. All rights reserved.]

KEYWORDS. Alcohol, sunflower oil, PUFA, lipids, body weight,hyperlipidemia

INTRODUCTION

Alcohol induced hyperlipidemia is a well known phenomenon thatresults in various metabolic disorders. Alcohol oxidation generates anexcess of reducing equivalents in liver, primarily as NADH, whichleads to the accumulation of lipids, resulting in fatty liver.1

Fat is an important dietary component, which affects both growth andhealth. It is widely accepted that a high level of fat in the diet is detri-mental to health. Replacing the traditional cooking fats, considered tobe atherogenic with refined vegetable oils promoted as ‘heart friendly’because of their PUFA content, has resulted in increased prevalence ofheart disease in India. Current data on dietary fats indicate that it is notjust the presence of PUFA but the type of PUFA that is important. Ahigh PUFA n-6 content and a high n-6/n-3 ratio in dietary fats is consid-

120 Journal of Nutraceuticals, Functional & Medical Foods


ered to be dangerous.2 The newer heart friendly oils like sunflower oilpossess this undesirable PUFA content and thus excess intake of thesevegetable oils is actually detrimental to health.

Alcoholics usually after a heavy binge of alcohol, take fried fooditems normally made up of PUFA. Our previous studies have shownthat the intake of sunflower oil along with alcohol aggravates hyper-lipidemia, especially when it is heated.3,4

Ferulic acid is a phytochemical, commonly found in fruits and veg-etables such as tomatoes, sweet corn, rice bran, etc.5 It is the predomi-nant bound phenolic acid in sweet corn, which constitutes about 78%of the total phenolic acids. Ferulic acid is a strong membrane antioxi-dant in humans and known to protect against cancer, cold, flu, influ-enza, skin aging and muscle wasting (Nutra pack report). The healthbenefits of ferulic acid (FA) is gaining a lot of attention nowadays inthe research world, but its antihyperlipidemic effect has not yet beenentirely proven.6 Hence the present investigation focuses on the anti-hyperlipidemic effects of ferulic acid during alcohol and PUFA in-duced toxicity. Since 20 mg/kg body weight FA was found to be veryeffective in our dose dependent study, we used the same dosage for allother experiments.

MATERIALS AND METHODS

Animals

Male Albino rats, Wistar strain of body weight ranging 140-160 gbred in Central Animal House, Rajah Muthiah Medical College, TamilNadu, India, fed on pellet diet (Agro Corporation Private Limited,Bangalore, India) were used for the study and water was given ad libi-tum. The standard pellet diet comprised 21% protein, 5% lipids, 4%crude fibre, 8% ash, 1% calcium, 0.6% phosphorus, 3.4% glucose, 2%vitamin and 55% nitrogen free extract (carbohydrates). It providesmetabolisable energy of 3600 K Cal/kg.

The animals were housed in plastic cages under controlled conditionsof 12 h light/12 h dark cycle, 50% humidity and at 30° ± 2°C. The ani-mals used in the present study were maintained in accordance with theguidelines of the National Institute of Nutrition, Indian Council of Med-ical Research, Hyderabad, India and approved by the Animal EthicalCommittee.

Rukkumani et al. 121


Material Used

Ethanol : Absolute ethanol (AR) was obtained from Hayman Pri-vate limited, England.

Heated PUF : Sunflower oil was subjected to heating at 180°C for 30minutes, twice (composition given in Table 1).3

Ferulic Acid : Ferulic acid was obtained from Sigma Aldrich PrivateLimited, Bangalore, India.

All other chemicals used were of analytical grade.

Experimental Design

Group 1(Control)

: Control rats

Group 2(Alcohol)

: Rats given 20% ethanol (7.9 g/kg body weight)7

orally using an intragastric tube.

Group 3(DPUFA)

: Rats given high fat diet (15% heated sunfloweroil)3 mixed with the diet.

Group 4(Alcohol + DPUFA)

: Rats given 20% ethanol + 15% heated sunfloweroil.3

Group 5(Alcohol + FA)

: Rats given ferulic acid (20 mg/kg body weight)dissolved in 20% ethanol.

Group 6(DPUFA + FA)

: Rats given 15% heated sunflower oil + ferulicacid (20 mg/kg body weight) dissolved in dis-tilled water.

Group 7(Alcohol + DP + FA)

: Rats given ferulic acid (20 mg/kg body weight)dissolved in 20% ethanol + 15% heated sun-flower oil.

Group 8(FA)

: Rats given ferulic acid (20 mg/kg body weight)dissolved in water.

All animals were maintained in isocalorific diet (508 K Cal/kg bodyweight/day) using glucose solution. At the end of the experimental pe-riod of 45 days, the rats were anaesthetised using light ether and sacri-ficed by cervical decapitation. Blood and tissues such as liver, heart,and kidney were immediately processed and used for various biochemi-cal estimations.



Biochemical Parameters

Lipids from plasma and tissues were extracted by the procedure ofFolch et al.,8 using chloroform:methanol mixture (2:1 v/v). Antihyper-lipidemic action of ferulic acid was assessed by analysing the levels ofcholesterol by Zlatkis et al. method9 using a reagent kit, triglycerides bythe method of Foster and Dunn,10 phospholipids by the method ofZilversmith and Davis11 and free fatty acids by the method of Falholtet al.12

Statistical Analysis

Statistical analysis was done by analysis of variance (ANOVA) fol-lowed by Duncan’s Multiple Range Test (DMRT). Values were consid-ered statistically significant when P � 0.05.


TABLE 1. Fatty Acid Composition of Sunflower Oil (percentage of fatty acid/goil)

S. No. Fatty Acid Raw Oil Heated Oil

1. 9:0 3OH - 0.27 ± 0.02

2. 10:0 1.10 ± 0.08 0.15 ± 0.01

3. 10:0 2OH - 0.34 ± 0.03

4. 10:0 3OH - 0.15 ± 0.01

5. 11:0 - 4.27 ± 0.39

6. 12:0 5.74 ± 0.53 2.20 ± 0.18

7. 13:0 0.76 ± 0.05 -

8. 14:0 1.11 ± 0.06 0.25 ± 0.02

9. 15:0 0.49 ± 0.04 0.30 ± 0.02

10. 16:0 17.93 ± 1.54 16.78 ± 1.59

11. 16:1 - 0.36 ± 0.03

12. 17:0 - 0.67 ± 0.05

13. 17:0 cyclo - 0.52 ± 0.04

14. 18:0 9.87 ± 0.85 9.92 ± 0.87

15. 18:2 60.22 ± 5.74 52.89 ± 4.65

16. 18:1 2OH - 1.82 ± 0.13

17. 19:0 2.17 ± 0.19 0.95 ± 0.05

18. 20:0 0.61 ± 0.04 1.56 ± 0.08

19. 20:1 - 6.78 ± 0.65

Values are mean ± S.D. of six values.


RESULTS

Table 2 shows the average weight gained by the animals during thetotal experimental period of 45 days. The weight gain was significantlyreduced in alcohol, ∆PUFA and alcohol + ∆PUFA treated rats as com-pared to control rats. Administration of FA to these rats significantlyimproved the weight gain when compared to untreated rats.

The levels of cholesterol (Table 4), triglycerides (Table 5) and freefatty acids (Table 6) in liver, heart and kidney, and plasma (Table 3)were significantly elevated in alcohol, ∆PUFA and alcohol + ∆PUFAtreated rats when compared to control rats. Treatment with ferulic acideffectively reduced their lipid levels. The levels of phospholipids (Table 7)were significantly decreased in liver and kidney and increased in plasma(Table 3) and heart of alcohol, ∆PUFA and alcohol + ∆PUFA treatedrats which were positively modulated by FA administration.

DISCUSSION

Both alcohol and PUFA are known to influence body weight. In alco-hol, ∆PUFA, and alcohol + ∆PUFA groups, there was a significant de-crease in weight gain when compared to normal. This may be because,


TABLE 2. Changes in Body Weight Gain (values are mean ± S.D. from 6 rats ineach group)

S. No. Groups Initial Weight (g) Final Weight (g) Weight gain (g)

1. Normal 148.500 ± 7.69 251.00 ± 8.72 102.500 ± 4.09ah

2. Alcohol 150.167 ± 7.17 200.833 ± 9.55 50.667 ± 4.08b

3. ∆PUFA 143.667 ± 6.07 203.833 ± 5.82 60.167 ± 3.19c

4. Alcohol + ∆PUFA 158.167 ± 5.01 200.167 ± 3.89 42.000 ± 2.89d

5. Alcohol + FA 155.000 ± 6.46 245.667 ± 8.38 90.667 ± 3.50ef

6. ∆PUFA + FA 155.000 ± 4.08 248.167 ± 6.36 93.167 ± 4.07fe

7. Alcohol + ∆PUFA + FA 153.333 ± 5.53 232.167 ± 7.38 78.833 ± 5.23g

8. FA 152.500 ± 8.54 251.000 ± 11.43 98.500 ± 5.13ha

ANOVA followed by DMRTValues not sharing the common superscript differ significantly at P � 0.05


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TABLE 4. Levels of Cholesterol (values are mean ± S.D. from 6 rats in eachgroup)

S. No. Groups Livermg/100 g tissue

Heartmg/100 g tissue

Kidneymg/100 g tissue

1. Control 314.667 ± 34.24ah 171.500 ± 15.18ah 349.333 ± 20.84afh

2. Alcohol 517.500 ± 46.02bcg 418.333 ± 39.33b 568.667 ± 32.45bc

3. ∆PUFA 522.333 ± 35.63cbg 383.333 ± 33.86cg 534.000 ± 45.29cbg

4. Alcohol + ∆PUFA 668.500 ± 57.89d 510.833 ± 51.42d 670.500 ± 60.05d

5. Alcohol + FA 409.500 ± 22.19ef 259.667 ± 15.58ef 404.833 ± 27.26ef

6. ∆PUFA + FA 382.500 ± 20.54fe 251.000 ± 15.66fe 388.833 ± 26.57faeh

7. Alcohol + ∆PUFA + FA 491.500 ± 38.92gbc 379.167 ± 34.27gc 485.667 ± 34.72gc

8. FA 317.167 ± 39.29ha 175.500 ± 10.48ha 342.333 ± 25.41haf


TABLE 5. Levels of Triglyerides (values are mean ± S.D. from 6 rats in eachgroup)




1. Control 330.500 ± 27.03ah 328.667 ± 17.53aefh 464.000 ± 26.69aefh

2. Alcohol 567.167 ± 47.89bc 466.667 ± 46.01bcg 705.167 ± 71.6bc

3. ∆PUFA 528.000 ± 48.19cbg 477.167 ± 38.33cbg 690.000 ± 45.39cb

4. Alcohol + ∆PUFA 622.333 ± 52.28d 598.833 ± 60.53d 795.833 ± 73.92d

5. Alcohol + FA 406.167 ± 24.15ef 357.667 ± 16.48eafh 519.833 ± 32.76eaf

6. ∆PUFA + FA 392.500 ± 35.95fe 353.000 ± 26.18faeh 505.333 ± 33.35fae

7. Alcohol + ∆PUFA + FA 493.333 ± 32.38gc 445.167 ± 30.01gbc 582.167 ± 31.28g

8. FA 315.667 ± 22.25ha 320.833 ± 18.43haef 457.000 ± 34.39ha




TABLE 6. Levels of Free Fatty Acid (values are mean ± S.D. from 6 rats in eachgroup)




1. Control 740.500 ± 44.59aefh 481.500 ± 39.56aefh 384.667 ± 33.16aefh

2. Alcohol 1043.000 ± 84.34bcg 732.167 ± 78.59bc 728.333 ± 71.67bc

3. ∆PUFA 1053.500 ± 105.49cbg 700.000 ± 78.92cbg 681.833 ± 46.18cbg

4. Alcohol + ∆PUFA 1204.167 ± 107.95d 846.500 ± 61.91d 847.167 ± 68.97d

5. Alcohol + FA 829.333 ± 30.28eafh 508.667 ± 58.03eafh 438.000 ± 44.69eafh

6. ∆PUFA + FA 808.000 ± 59.48faeh 506.500 ± 56.45faeh 426.167 ± 33.24faeh

7. Alcohol + ∆PUFA + FA 972.000 ± 98.33gbc 641.667 ± 58.45gc 655.000 ± 41.47gc

8. FA 735.667 ± 69.99haef 472.000 ± 34.37haef 380.667 ± 38.42haef


TABLE 7. Levels of Phospholipids (values are mean ± S.D. from 6 rats in eachgroup)




1. Control 1708.833 ± 173.38afh 1073.333 ± 103.18aefh 1555.000 ± 113.79aefh

2. Alcohol 1038.333 ± 104.00bcd 1489.667 ± 167.61bcd 1050.000 ± 79.06bc

3. ∆PUFA 1029.667 ± 94.45cbd 1497.333 ± 140.36cbd 983.333 ± 120.24cbd

4. Alcohol + ∆PUFA 875.833 ± 77.62dbc 1525.833 ± 179.29dbc 848.333 ± 63.69dc

5. Alcohol + FA 1518.333 ± 166.90efg 1161.667 ± 91.09eafgh 1445.000 ± 136.05eafh

6. ∆PUFA + FA 1583.333 ± 121.11faeh 1164.667 ± 72.63faegh 1466.667 ± 139.34faeh

7. Alcohol + ∆PUFA + FA 1365.000 ± 107.28ge 1274.167 ± 142.26gef 1264.167 ± 68.00g

8. FA 1711.667 ± 174.06haf 1076.167 ± 111.16haef 1508.333 ± 158.92haef



alcohol due to its profound effect on nutrient economy produces mal-absorption of vitamins, nutritional imbalance and reduces food intake13

and thus tends to decrease body weight. It has been demonstrated thatthe ingestion of oxidized lipids causes profound alteration in membranecomposition, fluidity, and function.14 Thus, both alcohol and ∆PUFAcause significant liver damage. Liver being the seat for the metabolismof proteins, lipids and carbohydrates is severely affected leading to or-gan dysfunction and thus weight loss. On treatment with ferulic acidthere was a significant improvement because the functional capacity ofthe liver is restored by FA. FA is now widely used in herbal health sup-plement (Nutra pack). Reports of this company state that the supple-mentation of FA along with weight training improves strength andincreases lean muscle mass. Moreover, FA by its antioxidant potentialmight have reduced the damage of liver and improved the body weight.

Marked alteration in lipid metabolism has been reported in chronicethanol feeding.15 Alcohol is known to alter lipid metabolism in theliver and thus elevate the lipid levels in extrahepatic tissues.

The interaction of ethanol with lipid metabolism is complex. Whenethanol is present it becomes the preferred fuel for the liver and dis-places fat as a source of energy, blocking fat oxidation, resulting in fataccumulation.16 In this context, number of reports show that plasma andtissue lipid levels increase on alcohol consumption.17 Remla et al.18

have reported that administration of ethanol to rats changes the metabo-lism of lipids. Our observations also show marked changes in lipids dur-ing alcohol ingestion.

Ethanol administration is known to enhance the synthesis of choles-terol19 and fatty acids,20 leading to their accumulation in liver. The in-creased cholesterol during alcohol ingestion is due to increased β-hydroxymethyl glutaryl CoA (HMG CoA) reductase activity by ethanol, whichis the rate-limiting step in cholesterol biosynthesis.21 Reports haveshown that diet rich in PUFA stimulates the production of chylomicronsby the intestine22 and thus elevate cholesterol levels. Moreover, Nara-simhamurthy and Raina23 have found higher plasma cholesterol levelsin thermally oxidized oil fed group. These reports are in agreement withour findings that cholesterol levels are significantly increased in alco-hol, ∆PUFA, and alcohol + ∆PUFA treated groups.

Fielding et al.24 have found the increased plasma TG concentrationsafter acute ethanol ingestion. The increased NADH/NAD+ ratio duringalcohol intake enhances the concentration of α-glycerophosphate, whichfavors hepatic TG accumulation by trapping fatty acids. In vitro, alco-



hol has been shown to exert a direct effect on myocardial lipid metabo-lism, causing an increase in fatty acid esterification and a decrease inoxidation, thus accumulating TG. The increased TG levels after PUFAingestion can be attributed to the increased availability of FFA foresterification. Since the availability of FFA is more in alcohol + ∆ PUFAgroup, the TG levels are also comparatively higher.

Phospholipids are the vital components of biomembrane. They arethe primary targets of peroxidation and can be altered by ethanol.25 Thedecrease in the levels of phospholipids in liver and kidney may be due toincreased activity of phospholipases in these tissues. It has also beensuggested that the decreased levels of phospholipids are due to in-creased degradation of muscle phospholipids. Earlier studies have dem-onstrated that chronic exposure to ethanol may lead to progressiveincrease in membrane phospholipase A2 activity.26 Jaya et al.27 have re-ported a decrease in phospholipid content in liver and kidney of alcoholfed rats. These findings corroborate, the decrease in phospholipids inour study. The increased levels of PL in heart may be due to the in-creased availability of FFA. Since PUFA is a component of PL, the in-creased PUFA intake may also increase the levels of PL in heart.

The free fatty acid levels are enhanced in alcohol fed group, whichmay be attributed to increased formation of acetate, which inturn formFFA. The increased NADH/NAD+ ratio also favors fatty acid synthe-sis.28 Increased FFA in ∆ PUFA and alcohol + ∆ PUFA group may bedue to the increased membrane lipid breakdown. The increased dietaryPUFA, may also eventually increase the FFA levels.

Treatment with ferulic acid effectively reduced the lipid levels. Thismay be attributed to the effective antioxidant property of ferulic acid.Reports have shown that ferulic acid is effective against lipid peroxi-dation induced by Fe2+.29 UV absorption of FA catalyses stable phenoxyradical formation and thereby potentiates its ability to terminate freeradical chain reaction. By virtue of effectively scavenging deleteriousradicals and suppressing oxidative reactions, ferulic acid is shown as animportant antioxidant.30

Moreover, ferulic acid possesses distinct structural motifs (Figure 1)that can possibly contribute to the antioxidant potential of this compound.The presence of e� donating groups on the benzene ring (3-methoxy andmore importantly 4-hydroxy) of FA helps in terminating the free radicalchain reactions.31 The presence of carboxylic acid group with adjacentunsaturated C-C double bond can provide additional attack site for thefree radicals thus preventing them from attacking the membrane. More-over, the carboxylic acid group could facilitate the anchoring of ferulic



acid into the lipid bilayer providing some protection to membraneagainst lipid peroxidation.

Thus, ferulic acid effectively prevents lipid peroxidation and protectsthe membrane from damage and prevents the release of FFA from themembrane. FFA being the substrate for other lipids, its decrease may re-flect on the levels of other lipids.

In our study ferulic acid effectively reduced the levels of cholesterol.FA is a potent antioxidant and prevents LDL oxidation induced by cop-per ions and facilitates the uptake and degradation of cholesterol by theliver.32 In this context, FA was also found to be effective in treatingischemic stroke in China.33 Moreover, reports have shown that γ-oryzanol,a mixture of ferulic acid can lower the cholesterol level in blood andlower the incidence of coronary heart disease. In Japan, it has been usedas a natural antioxidant in foods, beverages, and cosmetics.34

From the results obtained, we could conclude that ferulic acid is es-sential to maintain health and fight against alcohol and PUFA inducedhyperlipidemia. It acts by different mechanisms and elicits a significanteffect on lipid profiles. In future, ferulic acid may become a promisingcandidate as an effective antihyperlipidemic drug.

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OH

OCH3

O� O

Ferulic acid (FA)

FIGURE 1


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