he pa to toxicity

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General Mechanism of Toxin

induced cell Damage and Death

Hepatotoxicity


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The liver plays a central role in transforming andclearing chemicals and is susceptible to thetoxicity from these agents. Certain medicinalagents, when taken in overdoses and sometimeseven when introduced within therapeutic ranges,may injure the organ. Other chemical agents, suchas those used in laboratories and industries,natural chemicals (e.g., microcystins) and herbal

remedies can also induce hepatotoxicity.Chemicals that cause liver injury are calledhepatotoxins.


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The human body identifies almost all drugs as foreignsubstances (i.e. xenobiotics) and subjects them to variouschemical processes (i.e. metabolism) to make them suitablefor elimination. This involves chemical transformations to(a) reduce fat solubility and (b) to change biologicalactivity. Although almost all tissues in the body have someability to metabolize chemicals, smooth endoplasmicreticulum in the liver is the principal "metabolic clearinghouse" for both endogenous chemicals (e.g., cholesterol,steroid hormones, fatty acids, proteins, and exogenoussubstances (e.g., drugs, alcohol).[4] The central role playedby liver in the clearance and transformation of chemicalsmakes it susceptible to drug-induced injury


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Drug metabolism is usually divided into two phases: phase1 and phase 2.

Phase 1 reaction is thought to prepare a drug for phase 2.However many compounds can be metabolized by phase 2

directly. Phase 1 reaction involves oxidation, reduction,hydrolysis, hydration and many other rare chemicalreactions. These processes tend to increase water solubilityof the drug and can generate metabolites which are morechemically active and potentially toxic. Most of phase 2reactions take place in cytosol and involve conjugation withendogenous compounds via transferase enzymes.Chemically active phase 1 products are rendered relativelyinert and suitable for elimination by this step.


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Cytochrome P-450 A group of enzymes located in the endoplasmic

reticulum, known as cytochrome P-450, is themost important family of metabolizing enzymesin the liver. Cytochrome P-450 is the terminaloxidase component of an electron transport chain.It is not a single enzyme, but rather consists of aclosely related family of 50 isoforms; six of themmetabolize 90% of drugs. There is a tremendous

diversity of individual P-450 gene products, andthis heterogeneity allows the liver to performoxidation on a vast array of chemicals (includingalmost all drugs) in phase 1


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Three important characteristics of the P450 systemhave roles in drug-induced toxicity :

1. Genetic diversity: Each of the P-450 proteins is unique and accounts

(to some extent) for the variation in drug

metabolism between individuals. Geneticvariations ( polymorphism ) in P-450 metabolismshould be considered when patients exhibitunusual sensitivity or resistance to drug effects at

normal doses. Such polymorphism is alsoresponsible for variable drug response amongpatients of differing ethnic backgrounds.
http://en.wikipedia.org/wiki/Polymorphism_(biology)http://en.wikipedia.org/wiki/Polymorphism_(biology)


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2.Change in enzyme activity:

Many substances can influence the P-450 enzymemechanism. Drugs interact with the enzyme family inseveral ways. Drugs that modify cytochrome P-450enzyme are referred to as either inhibitors or inducers.Enzyme inhibitors block the metabolic activity of oneor several P-450 enzymes. This effect usually occursimmediately. On the other hand, inducers increase P-450 activity by increasing its synthesis. Depending onthe inducing drug's half life, there is usually a delaybefore enzyme activity increases


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Cytochrome P-450 enzyme induction and inhibition [6][7][8]

Potentinducers

Potentinhibitors

Substrates

Rifampicin ,Carbamazepine ,Phenobarbital ,Phenytoin

Amiodarone ,cimetidine ,ciprofloxacin ,fluconazole ,fluoxetine ,erythromycin ,isoniazid ,diltiazem

Caffeine ,clozapine ,omeprazole ,losartan ,

theophylline


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3. Competitive inhibition:

Some drugs may share the same P-450specificity and thus competitively block theirbio transformation. This may lead toaccumulation of drugs metabolized by theenzyme. This type of drug interaction may alsoreduce the rate of generation of toxic substrate


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Mechanism of liver damage

Factors influencingdrug induced hepatotoxicity [10]

Age Ethnicity and race Gender Nutritional status Underlying liver disease Renal function Pregnancy

Duration and dosage of drug Enzyme induction Drug-to-drug interaction


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Drugs continue to be taken off the market due to late discovery of

hepatotoxicity. Due to its unique metabolism and close relationshipwith the gastrointestinal tract, the liver is susceptible to injury fromdrugs and other substances. 75% of blood coming to the liver arrives

directly from gastrointestinal organs and then spleen via portal veinswhich bring drugs and xenobiotics in near-undiluted form. Severalmechanisms are responsible for either inducing hepatic injury orworsening the damage process. Many chemicals damagemitochondria, an intracellular organelle that produce energy. Itsdysfunction releases excessive amount of oxidants which, in turn,

injure hepatic cells. Activation of some enzymes in the cytochromeP-450 system such as CYP2E1 also lead to oxidative stress. Injuryto hepatocyte and bile duct cells lead to accumulation of bile acidinside liver. This promotes further liver damage..


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Chemicals produce a wide variety of clinical and pathological hepaticinjury. Biochemical markers (e.g. alanine transferase, alkaline phosphataseand bilirubin) are often used to indicate liver damage. Liver injury isdefined as a rise in either (a) ALT level more than three times of upper limitof normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubinlevel more than twice ULN when associated with increased ALT or ALP.Liver damage is further characterized into hepatocellular (predominantlyinitial Alanine transferase elevation) and cholestatic (initial alkalinephosphatase rise) types. However they are not mutually exclusive andmixed types of injuries are often encountered.

Specific histo-pathological patterns of liver injury from drug-induceddamage are discussed below.


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Zonal Necrosis

This is the most common type of drug-inducedliver cell necrosis where the injury is largelyconfined to a particular zone of the liverlobule. It may manifest as a very high level of ALT and severe disturbance of liver functionleading to acute liver failure

Causes include: Paracetamol , carbon tetrachloride
http://en.wikipedia.org/wiki/Paracetamolhttp://en.wikipedia.org/wiki/Carbon_tetrachloridehttp://en.wikipedia.org/wiki/Carbon_tetrachloridehttp://en.wikipedia.org/wiki/Paracetamol


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Steatosis Hepatotoxicity may manifest as triglyceride accumulation

which leads to either small droplet (microvesicular) or largedroplet (macrovesicular) fatty liver. There is a separate typeof steatosis where phospholipid accumulation leads to apattern similar to the diseases with inherited phospholipidmetabolism defects (e.g. Tay-Sachs disease )

Causes: (a) Microvesicular: Aspirin (Reye's syndrome ), ketoprofen ,

tetracycline (especially if expired)

(b) Macrovesicular: Acetamenophen , methotrexate (c) Phospholipidosis: Amiodarone , total parenteral nutrition
http://en.wikipedia.org/wiki/Steatosishttp://en.wikipedia.org/wiki/Tay-Sachs_diseasehttp://en.wikipedia.org/wiki/Aspirinhttp://en.wikipedia.org/wiki/Reye's_syndromehttp://en.wikipedia.org/wiki/Ketoprofenhttp://en.wikipedia.org/wiki/Tetracyclinehttp://en.wikipedia.org/wiki/Acetamenophenhttp://en.wikipedia.org/wiki/Methotrexatehttp://en.wikipedia.org/wiki/Amiodaronehttp://en.wikipedia.org/wiki/Total_parenteral_nutritionhttp://en.wikipedia.org/wiki/Total_parenteral_nutritionhttp://en.wikipedia.org/wiki/Total_parenteral_nutritionhttp://en.wikipedia.org/wiki/Total_parenteral_nutritionhttp://en.wikipedia.org/wiki/Total_parenteral_nutritionhttp://en.wikipedia.org/wiki/Amiodaronehttp://en.wikipedia.org/wiki/Methotrexatehttp://en.wikipedia.org/wiki/Acetamenophenhttp://en.wikipedia.org/wiki/Tetracyclinehttp://en.wikipedia.org/wiki/Ketoprofenhttp://en.wikipedia.org/wiki/Reye's_syndromehttp://en.wikipedia.org/wiki/Aspirinhttp://en.wikipedia.org/wiki/Tay-Sachs_diseasehttp://en.wikipedia.org/wiki/Tay-Sachs_diseasehttp://en.wikipedia.org/wiki/Tay-Sachs_diseasehttp://en.wikipedia.org/wiki/Steatosis


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Granuloma

Drug-induced hepatic granulomas are usuallyassociated with granulomas in other tissuesand patients typically have features of systemicvasculitis and hypersensitivity. More than 50drugs have been implicated.

Causes: Allopurinol , phenytoin , isoniazid , quinine ,

penicillin , quinidine
http://en.wikipedia.org/wiki/Granulomahttp://en.wikipedia.org/wiki/Allopurinolhttp://en.wikipedia.org/wiki/Phenytoinhttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Quininehttp://en.wikipedia.org/wiki/Penicillinhttp://en.wikipedia.org/wiki/Quinidinehttp://en.wikipedia.org/wiki/Quinidinehttp://en.wikipedia.org/wiki/Penicillinhttp://en.wikipedia.org/wiki/Quininehttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Phenytoinhttp://en.wikipedia.org/wiki/Allopurinolhttp://en.wikipedia.org/wiki/Granuloma


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Case: Acetaminophen Acetaminophen (3D s tructure) overdo se is the most common cause of drug-

induced liver disease. Acetaminophen (paracetamol, also known by the brandname Tylenol and Panadol) is usually well tolerated in prescribed dose, butoverdo se is the most common cause of drug-induced liver disease and acute liverfailure worldwide. Damage to the liver is not due to the drug itself but to a toxicmetabolite ( N-acetyl- p-benzoquinone imine NAPQI, or NABQI) which is producedby cytochrome P-450 enzymes in the liver. In normal circ umstances, thismetabolite is detoxified by conjugating with glutathione in phase 2 reaction. In anoverdose, a large amount of NAPQI is generated whic h overwhel ms thedetoxification process and leads to liver cell damage. Nitric oxide also plays role ininducing toxicity. The risk of liver injury is influenced by several factors includingthe dose ingested, concurrent alcohol or other drug intake, interval betweeningestion and antidote, etc. The dose toxic to the liver is quite variable from personto person and is smaller in chronic alcoholics. Measurement of blood level is

important in asses sing prognosis , higher levels predicting a worse prognosis.Administration of Acetylcysteine , a precursor of glutathione, can limit the severit yof the liver damage by capturing the toxic NAPQI. Those who develop acute liverfailure can still recover s pontaneously, b ut m ay require tr ansplantation if poorprognostic signs such as encephalopathy or coagulopathy is present
http://en.wikipedia.org/wiki/Acetaminophenhttp://en.wikipedia.org/wiki/Acetaminophenhttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Glutathionehttp://en.wikipedia.org/wiki/Glutathionehttp://en.wikipedia.org/wiki/Nitric_oxidehttp://en.wikipedia.org/wiki/Nitric_oxidehttp://en.wikipedia.org/wiki/Acetylcysteinehttp://en.wikipedia.org/wiki/Acetylcysteinehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Prognostichttp://en.wikipedia.org/wiki/Prognostichttp://en.wikipedia.org/wiki/Encephalopathyhttp://en.wikipedia.org/wiki/Coagulopathyhttp://en.wikipedia.org/wiki/Prognostichttp://en.wikipedia.org/wiki/Encephalopathyhttp://en.wikipedia.org/wiki/Coagulopathyhttp://en.wikipedia.org/wiki/Coagulopathyhttp://en.wikipedia.org/wiki/Encephalopathyhttp://en.wikipedia.org/wiki/Prognostichttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acetylcysteinehttp://en.wikipedia.org/wiki/Nitric_oxidehttp://en.wikipedia.org/wiki/Glutathionehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acute_liver_failurehttp://en.wikipedia.org/wiki/Acetaminophen


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Glucocorticoids

Glucocorticoids are so named due to theireffect on the carbohydrate mechanism. Theypromote glycogen storage in the liver. Anenlarged liver is a rare side effect of long-termsteroid use in children. The classical effect of prolonged use both in adult and paediatric

population is steatosis.
http://en.wikipedia.org/wiki/Paediatrichttp://en.wikipedia.org/wiki/Paediatric


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Isoniazid

Isoniazide (INH) is one of the most commonlyused drugs for tuberculosis; it is associatedwith mild elevation of liver enzymes in up to20% of patients and severe hepatotoxicity in1-2% of patients.


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Natural products Examples include many amanita mushrooms

(particularly the destroying angels), andaflatoxins.[citation needed]

Industrial toxin Examples include arsenic, carbon tetrachloride, and

vinyl chloride.Herbal and alternative remedies Examples include Ackee fruit, Bajiaolian, Camphor,Copaltra, Cycasin, Kava,[33] pyrrolizidine alkaloids,

Horse chestnut leaf, Valerian, Comfrey

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