Abstract
Acetaminophen is oxidized by cytochrome P450 to a reactive quinone imine, N-acetyl-p-benzoquinone imine, which is thought to be responsible for its hepatotoxic effects. 4-Hydroxyphenylacetone (4-HPA) is a structural analog of acetaminophen in which the amine group is replaced by a methylene group. Following a similar metabolic pathway, 4-HPA would be oxidized to form a reactive quinone methide intermediate. We compared the metabolism and toxicity of 4-HPA and acetaminophen in liver microsomes and precision-cut liver slices from male Sprague-Dawley rats. Both 4-HPA and acetaminophen formed glutathione conjugates in microsomal incubations. 4-HPA formed diastereomeric glutathione conjugates, which is consistent with the formation of an intermediate quinone methide. The rate of conjugate formation with 4-HPA was 8.5-fold greater than that with acetaminophen. In rat liver slices a concentration of 5 mM 4-HPA killed approximately 50% of hepatocytes after 6 hr of incubation, whereas acetaminophen was not toxic at concentrations up to 50 mM. N-Acetylcysteine protected slices from 4-HPA-induced toxicity, whereas phenobarbital enhanced metabolism and toxicity. In summary, 4-HPA is more hepatotoxic than acetaminophen, and this may be the result of differences in the metabolic rate and/or the type of reactive intermediate formed.
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