title: Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens.
abstract: The metabolic activation or inactivation of carcinogens varies considerably in human populations, and is partly genetically determined. 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. We have determined levels of DNA adducts in bladder cells and of 4-aminobiphenyl-haemoglobin 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.
authors.affiliation: Dipartimento di Scienze Biomediche e Oncologia Umana, University and Main Hospital, Torino, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Vineis
authors.forename: H
authors.initials: H
authors.lastname: Bartsch
authors.forename: N
authors.initials: N
authors.lastname: Caporaso
authors.forename: A M
authors.initials: AM
authors.lastname: Harrington
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: M T
authors.initials: MT
authors.lastname: Landi
authors.forename: C
authors.initials: C
authors.lastname: Malaveille
authors.forename: P G
authors.initials: PG
authors.lastname: Shields
authors.forename: P
authors.initials: P
authors.lastname: Skipper
authors.forename: G
authors.initials: G
authors.lastname: Talaska
mesh_terms: D000107:Acetylation; D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D002110:Caffeine / Q000652:urine; D002274:Carcinogens, Environmental / Q000378:metabolism* / Q000493:pharmacokinetics; D003367:Cotinine / Q000652:urine; D004249:DNA Damage; D005838:Genotype; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000652:urine; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D012907:Smoking; D001743:Urinary Bladder / Q000473:pathology
chemical_list: D002274:Carcinogens, Environmental; D006454:Hemoglobins; C062091:hemoglobin, 4-aminobiphenyl-; D002110:Caffeine; D009538:Nicotine; D001191:Arylamine N-Acetyltransferase; D003367:Cotinine