Interactions between genetic polymorphism of cytochrome P450-1B1, sulfotransferase 1A1, catechol-o-methyltransferase and tobacco exposure in breast cancer risk

Genetic polymorphisms of enzymes involved in the metabolism of xenobiotics and estrogens might play a role in breast carcinogenesis related to environmental exposures. In a case-only study on 282 women with breast cancer, we studied the interaction effects (ORi) between smoking habits and the gene polymorphisms of Cytochrome P450 IBI (Val432Leu CYPIBI), Phenol-sulfotransferase IAI (Arg213His SULTIAI) and Catechol-O-methyltransferase (Val I 58Met COMT). The smokers carrying the Val CYP IBI allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi=2.32, 95%CI: 1.00-5.38). Also, the smokers carrying the His SULTIAI allele associated with a low sulfation activity had a 2-fold excess risk compared to never smokers carrying Arg/Arg SUTIAI common genotype (ORi= 2.55, 95%CI: 1.21-5.36). The His SULTIAI allele increased the risk only in premenopausal patients. The Met COMT allele with a lower methylation activity than Val COMT did not modify the risk among smokers. The excess risk due to joint effect could result from a higher exposure to activated tobacco-compounds for women homo/ heterozygous for the Val CYPIBI allele. Also, a lower sulfation of the tobacco carcinogens among women with His SULTIAI could increase exposure to genotoxic compounds. Alternatively, the Val CYPIBI or His SULTIAI allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradial) among smokers. Our study showed that gene polymorphisms of CYPIBI and SULTIAI induce an individual susceptibility to breast cancer among current smokers. (C) 2003 Wiley-Liss, Inc.