Drug or more commonly reactive metabolites generated by
CYPs can covalently bind to tissue macromolecules (such as proteins or DNA) to
cause tissue toxicity. Because of the reactive nature of these metabolites
covalent binding often occurs close to the site of production; this is
typically the liver, although CYPs are found in other tissues as well.
The
most common cause of drug-induced hepatotoxicity is acetaminophen overdosage.
Normally, reactive metabolites are detoxified by combining with hepatic
glutathione. When glutathione becomes exhausted, the metabolites bind instead
to hepatic protein, with resultant hepatocyte damage. The hepatic necrosis
produced by the ingestion of acetaminophen can be prevented, or at least
attenuated, by the administration of substances such as N-acetylcysteine that
reduce the binding of electrophilic metabolites to hepatic proteins. The risk of
hepatic necrosis is increased in patients receiving drugs such as phenobarbital
or phenytoin that increase the rate of drug metabolism or ethanol that exhaust
glutathione stores. Such toxicity has even occurred with therapeutic dosages,
so patients at risk through these mechanisms should be warned.
Source:
Harrison_s_Principles_of_Internal_Medicine_16th_Edition
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