Molecular Pharmacology, Vol 11, 159-165, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Genetic Differences in the Aromatic Hydrocarbon-Inducible N-Hydroxylation of 2-Acetylaminofluorene and Acetaminophen-Produced Hepatotoxicity in Mice

¹ Section on Developmental Pharmacology, Laboratory of Biomedical Sciences, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20014

The genetically mediated presence or absence of induction, as well as the magnitude of induction, of aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity is highly correlated (p < 0.001) with the N-hydroxylation of 2-acetylaminofluorene in the livers of C57BL/6N and DBA/2N inbred mice treated with the microsomal enzyme inducers 3-methylcholanthrene, -naphthoflavone, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and sodium phenobarbital. The extent of hepatotoxicity caused by acetaminophen (p-hydroxyacetanilide) administered intraperitoneally to these two strains of mice is also highly associated with both aromatic hydrocarbon-inducible monooxygenase "activities": aryl hydrocarbon hydroxylase and acetylarylamine N-hydroxylase. We suggest that cytochrome P₁450 is involved with the aromatic hydrocarbon-inducible N-hydroxylase activity and that these genetic differences among inbred strains of mice offer a valuable experimental model system for studying the mechanism of hepatotoxicity and carcinogenicity among siblings of a defined genotype.