TY - JOUR T1 - Genetic Differences in 2-Acetylaminofluorene Mutagenicity <em>in vitro</em> Associated with Mouse Hepatic Aryl Hydrocarbon Hydroxylase Activity Induced by Polycyclic Aromatic Compounds JF - Molecular Pharmacology JO - Mol Pharmacol SP - 225 LP - 233 VL - 12 IS - 2 AU - JAMES S. FELTON AU - DANIEL W. NEBERT AU - SNORRI S. THORGEIRSSON Y1 - 1976/03/01 UR - http://molpharm.aspetjournals.org/content/12/2/225.abstract N2 - 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. ACKNOWLEDGMENT We appreciate very much the expert technical assistance of Roy C. Levitt. ER -