Genetic differences in 2-aminofluorene pharmacokinetics between intact C57BL/6J and A/J mice

Studies of genetically determined differences in arylamine acetylation with the model carcinogen 2-aminofluorene in C57BL/6J and A/J inbred mouse strains showed that individual differences in the pharmacokinetics of 2-aminofluorene were dependent on differences in 2-aminofluorene N-acetyltransferase activity in liver and blood. Elimination rates of 2-aminofluorene from blood of mice administered a single ip dose of 30, 50, or 100 mg/kg of 2-aminofluorene were dose-dependent in both strains. At a dose of 100 mg/kg, the average rate of 2-aminofluorene elimination was approximately three times faster in rapid acetylator (C57BL/6J) mice than in slow acetylator (A/J) mice (0.36 +/- 0.02 hr-1 vs. 0.12 +/- 0.02 hr-1), and that in B6AF1 mice was intermediate (0.24 +/- 0.02 hr-1) to the parental lines. These results support previous observations that acetylation of arylamines is controlled by intermediate dominant inheritance of two major alleles at a single locus. Comparison of the average rate of elimination of 2-aminofluorene from blood of the congenic mouse line, A.B6-NATr, (0.27 +/- 0.05 hr-1) which has the rapid acetylator allele placed on the A/J background provided evidence that modifying genes of the A/J mouse significantly reduced the effect of the rapid acetylator allele on the rate of 2-aminofluorene elimination. A trend was observed toward a greater apparent volume of distribution for 2-aminofluorene in A/J than in C57BL/6J mice.