Tissue Lesions Liver Necrosis

Carbon tetrachloride. A hepatotoxic solvent which causes centrilobular necrosis and fatty liver; liver cirrhosis and tumours and kidney

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damage after chronic exposure. It is metabolized in liver by cytochrome P-450 by reduction to a free radical which causes lipid peroxidation which destroys membranes and produces toxic aldehydes such as 4-hydroxynonenal. The rough endoplasmic reticulum is damaged, hence protein synthesis is disrupted and this may cause the fatty liver. The free radical also binds to protein and lipid. Cytochrome P-450 (1A2) is also selectively destroyed and so a small dose protects against the hepatotoxicity of a subsequent large dose.

Paracetamol. Widely used analgesic which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses due to impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with glutathione, but depletes it after an excessive dose and then binds to liver protein. Metabolic activation is catalysed by cytochrome P-450, and the particular isoform (2E1, 1A2 or 3A4) depends on the dose. Antidote is N-acetylcysteine which promotes the synthesis of new glutathione and may also be involved in the detoxication. Bromobenzene. A hepatotoxic industrial solvent which causes centrilobular liver necrosis. It is metabolized in the liver to a reactive epoxide (3,4) which is detoxified by conjugation with glutathione, leading to excretion of a mercapturic acid. Depletion of glutathione with an excess dose leads to binding of the reactive epoxide to liver protein and necrosis. Glutathione conjugate is excreted as a mercapturic acid in urine. Epoxide hydrolase detoxifies and induction may also detoxify by increasing metabolism to a less reactive epoxide (2,3). Bromobenzene can also cause kidney damage which may be due to diglutathionyl conjugate of 2-bromohydroquinone.

Isoniazid and iproniazid. These substituted hydrazine drugs may both cause liver damage after therapeutic doses. With isoniazid a mild hepatic dysfunction may occur in 10-20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhydrazine and isopropylhydrazine respectively) which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhydrazine is detoxified by acetylation.

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