Role of the acetylation polymorphism in determining susceptibility of cultured rabbit hepatocytes to DNA damage by aromatic amines.
In humans and rabbits, differences in the rate of N-acetylation of aromatic amines are under polymorphic genetic control. Individuals are classified as either rapid or slow acetylators. In the current study, the relationship between acetylator phenotype and susceptibility to the genotoxicities of benzidine, 4-aminobiphenyl, 4,4'-methylenebis-2-chloroaniline, and 2-naphthylamine was investigated. Cultured hepatocytes isolated from rapid and slow acetylator rabbits were exposed to a dose range of the aromatic amines, and genotoxicity was determined by the autoradiographic measurement of DNA repair synthesis. Hepatocytes from rapid acetylator rabbits were more susceptible to the genotoxic effect of benzidine than were cells from slow acetylators. 4-Aminobiphenyl and 4,4'-methylenebis-2-chloroaniline were both weakly genotoxic, but no clear correlation was seen with acetylator phenotype. No genotoxicity was observed with 2-naphthylamine. These results thus demonstrate that differences in acetylation rates can affect the genotoxicity of benzidine. This study provides further evidence for the role of the genetically determined acetylator polymorphism in determining susceptibility to the effects of certain aromatic amine carcinogens. Since the acetylator polymorphism is a human trait, a similar susceptibility may be displayed in humans.
D015081:2-Naphthylamine / Q000633:toxicity; D000107:Acetylation; D000611:Aminobiphenyl Compounds / Q000633:toxicity*; D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D001560:Benzidines / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D008099:Liver / Q000187:drug effects*; D008753:Methylenebis(chloroaniline) / Q000633:toxicity*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011817:Rabbits
D000611:Aminobiphenyl Compounds; D001559:Benzhydryl Compounds; D001560:Benzidines; C006757:4-biphenylamine; D008753:Methylenebis(chloroaniline); D004247:DNA; D015081:2-Naphthylamine