Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens

THE metabolic activation or inactivation of carcinogens varies considerably in human populations, and is partly genetically determined 1,2 . Inter-individual variability in the susceptibility to carcinogens may be particularly important at low degrees of environmental exposure. Examples of probable human carcinogens that present widespread low-dose exposures are environmental tobacco smoke and diesel exhaust 3,4 . We have determined levels of DNA adducts in bladder cells and of 4-aminobipheny7l–haemo-globin adducts in 97 volunteers, together with the N -acetylation non-inducible phenotype, the corresponding genotype, and the levels of nicotine–cotinine in the urine. We find that among the slow acetylators, 4-aminobiphenyl adducts were higher than in rapid acetylators at low or null nicotine–cotinine levels, whereas the difference between slow and rapid acetylators was less evident at increasing nicotine–cotinine levels. The N -acetyltransferase genotype is highly predictive of the acetylation phenotype. Our results indicate that the clearance of low-dose carcinogens is decreased in the genetically based slow-acetylator phenotype. Such genetic modulation of low-dose environmental risks is relevant to ‘risk assessment’ procedures.