Metabolism and toxicity of 4-hydroxyphenylacetone in rat liver slices: comparison with acetaminophen.
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.
Thompson
D C
DC
Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University Health Science Center, College Station 77843-1114, USA.
Perera
K
K
London
R
R
D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity*; D000096:Acetone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
C102899:4-hydroxyphenylacetone; D018712:Analgesics, Non-Narcotic; D000096:Acetone; D000082:Acetaminophen; D005978:Glutathione