Vineis P, Bartsch H, Caporaso N, Harrington A M, Kadlubar F F, Landi M T, Malaveille C, Shields P G, Skipper P, Talaska G
Dipartimento di Scienze Biomediche e Oncologia Umana, University and Main Hospital, Torino, Italy.
Nature. 1994 May 12;369(6476):154-6. doi: 10.1038/369154a0.
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.
致癌物的代谢活化或失活在人群中差异很大，部分由基因决定。在低水平环境暴露下，个体对致癌物易感性的个体间差异可能尤为重要。存在广泛低剂量暴露的可能人类致癌物的例子有环境烟草烟雾和柴油废气。我们测定了97名志愿者膀胱细胞中的DNA加合物水平以及4-氨基联苯-血红蛋白加合物水平，同时测定了N-乙酰化非诱导型表型、相应基因型以及尿液中尼古丁-可替宁的水平。我们发现，在慢乙酰化者中，在低或无尼古丁-可替宁水平时，4-氨基联苯加合物高于快乙酰化者，而在尼古丁-可替宁水平升高时，慢乙酰化者与快乙酰化者之间的差异则不那么明显。N-乙酰转移酶基因型高度可预测乙酰化表型。我们的结果表明，基于遗传的慢乙酰化者表型中低剂量致癌物的清除率降低。这种低剂量环境风险的基因调节与“风险评估”程序相关。
