Toxicity of the heterocyclic amine batracylin: investigation of rodent N-acetyltransferase activity and potential contribution of cytochrome P450 3A

The heterocyclic amine, batracylin (BAT), is genotoxic and several lines of evidence suggest that acetylation is one step in the formation of a DNA-da maging product. The variation in susceptibility to BAT toxicity observed be tween rats and mice has also been linked to the acetylated product. BAT N-a cetyltransferase (NAT) activity was determined in rat and mouse hepatic cyt osols. Formation of acetylbatracylin (ABAT) was 6 times greater in F-344 he patic samples compared to either mouse strain, while hepatic BAT NAT activi ties were similar in C57B1/6 and A/J mice. No deacetylation of ABAT was det ected. In contrast, 2-aminofluorene NAT activity in C57B1/6 hepatic cytosol was twice that of the A/J strain and activities in both strains of mice we re greater than in rat. Deacetylation of 2-acetylaminofluorene was detected in both species with enzyme activities in C57B1/6 > A/J > F-344. Hepatocyt es from the F-344 rats, the species most sensitive to BAT toxicity, were us ed to investigate the contribution of other biotransformation reactions to BAT cytotoxicity. Leakage of cellular lactate dehydrogenase was greater in hepatocytes from male rats than from females, increased on in vivo exposure to dexamethasone, and decreased in the presence of troleandomycin, suggest ing that CYP3A-mediated biotransformation of BAT is involved in the formati on of a cytotoxic product. When phenol red, a substrate for UDP-glucuronsyl transferase (UDPGT), was absent from the medium, BAT cytotoxicity was reduc ed. These data are consistent with a role for NAT, CYP, and UDPGT in the bi otransformation of BAT.