Determination of host genetic susceptibility to genotoxic chemicals in hepatocyte cultures.
The relationship between acetylator phenotype and genotoxicity, i.e., damage to DNA, has been investigated using freshly isolated hepatocytes, an in-vitro system representing the major organ of N-acetyltransferase (NAT) activity. Hepatocytes were isolated from rapid and slow acetylator rabbits by enzymatic perfusion of the liver. Unscheduled DNA synthesis (UDS), determined by autoradiography, was used as an indicator of DNA damage. Hydralazine (HDZ) elicited UDS in hepatocytes from slow acetylators but little or none in hepatocytes from rapid acetylators. However, hepatocytes from rapid acetylators were more sensitive to the effects of 2-aminofluorene (2-AF). A concentration of 10(-3) M 2-AF was toxic, and 10(-4) M elicited UDS in hepatocytes from rapid acetylators. Hepatocytes from slow acetylators showed UDS when exposed to 10(-3) M. No differences were observed between the two phenotypes in the amount of UDS elicited by 2-acetylaminofluorene. These results demonstrate a correlation between acetylator phenotype and genotoxicity of substrates of NAT. Moreover, as shown by the different responses to HDZ and 2-AF, the sensitive phenotype varies with chemical structure. Thus, the identification of phenotype-dependent differences in the amount of DNA damage in rabbit hepatocytes offers evidence for genetic susceptibility to genotoxic chemicals and indicates that a similar susceptibility would be displayed by humans who express the same polymorphism in NAT activity.
D000123:Acetyltransferases / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects; D005449:Fluorenes / Q000494:pharmacology; D006830:Hydralazine / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011817:Rabbits; D013411:Sulfadiazine / Q000378:metabolism
D005449:Fluorenes; D013411:Sulfadiazine; D006830:Hydralazine; C012177:2-aminofluorene; D000123:Acetyltransferases