Molecular Pharmacology, Vol 12, 225-233, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Genetic Differences in 2-Acetylaminofluorene Mutagenicity in vitro Associated with Mouse Hepatic Aryl Hydrocarbon Hydroxylase Activity Induced by Polycyclic Aromatic Compounds

¹ Section on Developmental Pharmacology, Neonatal and Pediatric Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20014

The genetically mediated difference in aromatic hydrocarbon-inducible hepatic aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity is associated with the metabolic activation of 2-acetylaminofluorene to a mutagen in vitro by liver fractions. With the use of"responsive" C57BL/6N and "nonresponsive" DBA/2N inbred strains and offspring from the appropriate crosses, the aromatic hydrocarbon-inducible hydroxylase activity appears to be expressed as an autosomal dominant trait, whereas 2-acetylaminofluorene mutagenicity in vitro appears to be expressed additively. With N-hydroxy-2-acetylaminofluorene added in vitro, no metabolic activation is necessary for mutagenesis to occur; however, mutagenicity is enhanced 20-40-fold in the presence of liver fractions. The metabolic activation of N-hydroxy-2-acetylaminofluorene to a frameshift mutagen in vitro is not associated with the genetically mediated difference in aromatic hydrocarbon responsiveness. We therefore suggest that the rate-limiting step of 2-acetylaminofluorene mutagenesis is its activation by cytochrome P₁450 to the N-hydroxy derivative, which is metabolized further to a much more mutagenic intermediate by a reaction independent of cytochrome P₁450-possibly a deacetylation reaction.

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ACKNOWLEDGMENT We appreciate very much the expert technical assistance of Roy C. Levitt.