No 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.

This study finds that the levels of two different carcinogen-DNA adducts vary in lung tissue (an important target tissue) in association with three separate genetic polymorphisms (i.e., CYP2D6, CYP2E1, and GSTM1). CYP2D6 and CYP2E1 genotypes are associated with higher 7-methyl-dGMP levels, while the GSTM1 null genotype is associated with higher numbers of PAH-dGMP adducts. These findings suggest that genetic polymorphisms are predictive of carcinogen-DNA adduct levels and would thus be predictive of an individual's lifetime response to carcinogen exposure.

Known breast-cancer risk factors account for only part of the variability in breast-cancer incidence. Tobacco smoke is not commonly considered a breast carcinogen, but many of its constituents, such as N-nitrosamines, are carcinogenic in laboratory animal studies. Herein, we assessed a cytochrome P4502E1 (CYP2E1) genetic polymorphism (a Dral restriction enzyme site in intron 6) as a risk factor for breast cancer in both premenopausal and postmenopausal women. Because N-nitrosamines are metabolically activated by CYP2E1, the risk among women smokers was investigated. Caucasian women were enrolled in a case-control study of breast cancer between 1986 and 1991. A subset of the women (219 premenopausal and 387 postmenopausal women) consented to phlebotomy. The allelic frequencies for the premenopausal women (D allele = 0.91 and C allele = 0.09) and postmenopausal women (D allele = 0.93 and C allele = 0.07) were similar to those previously reported. There was no statistically significant association between the CYP2E1 polymorphism and breast-cancer risk for premenopausal or postmenopausal women (adjusted odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.48, 2.24, and OR = 1.01, 95% CI = 0.55, 1.84, respectively). When the women were categorized as nonsmokers versus smokers (those who smoked more than one cigarette per week for more than 1 yr), premenopausal women with one or two C alleles who had a history of smoking were found to be at increased risk (unadjusted OR = 7.00, 95% CI = 0.75, 14.53, and adjusted OR = 11.09, 95% CI = 1.51, 81.41), although the number of study subjects with those genotypes was small. The small number of study subjects with a C allele precluded meaningful classification by level of smoking, but categorizing the smokers into two groups (above and below the median) also suggested an increased risk. Premenopausal women with the DD genotype and postmenopausal women with any genotype were not at increased risk. Breast-cancer risk was not related to the CYP2E1 genotype in either premenopausal nonsmokers or smokers (adjusted OR = 0.66, 95% CI = 0.20, 2.17, and OR = 2.13, 95% CI = 0.60, 7.59, respectively) or postmenopausal nonsmokers or smokers (OR = 0.90, 95% CI = 0.34, 2.35, and OR = 1.02, 95% CI = 0.46, 2.23, respectively), although the difference in the ORs for premenopausal nonsmokers and smokers suggests an increased risk for smokers. While there are limitations to this study, particularly related to the small number of subjects with the DC and CC genotypes, the study suggests that some women may be susceptible to tobacco smoke because of a CYP2E1 polymorphism. However, these results are preliminary and must be replicated.

Cardiovascular diseases are a major public health problem in Mississippi that is especially severe in African American residents, and the problem is growing worse each year. It is important to identify the determinants of and solutions for this enormous public health problem in Mississippi.