Relationship between the genetically determined acetylator phenotype and DNA damage induced by hydralazine and 2-aminofluorene in cultured rabbit hepatocytes.

The relationship between acetylation rates of rabbit hepatocytes and their susceptibility to genotoxicity by DNA-damaging chemicals that undergo N-acetylation was studied in primary cultures of hepatocytes from New Zealand White rabbits that have a genetically determined difference in acetylation rates. Hepatocytes from rapid and slow acetylator rabbits maintained in culture the difference in acetylation rates that existed in vivo, DNA repair, an index of DNA damage, was produced by hydralazine in hepatocytes from slow acetylator rabbits but not in those from rapid acetylators. In contrast to these results, hepatocytes from rapid acetylators were more sensitive than those from slow acetylators to toxicity from the carcinogen 2-aminofluorene and displayed greater amounts of DNA repair. The amount of DNA repair measured with either chemical was dose dependent. These phenotype-dependent differences in the genotoxicity of two DNA-damaging chemicals provide evidence for the role of the acetylation polymorphism as a factor in determining susceptibility to toxicity, and perhaps carcinogenicity, of these chemicals.