CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has a protecti ve effect on the incidence of colon neoplasia, However, polymorphisms in NS AID-metabolizing enzymes may alter this effect. NSAIDs, particularly aspiri n, are glucuronidated by UGT1A6 and some classes of NSAIDs are also metabol ized by cytochrome P450 (CYP) 2C9, Both of these enzymes have slow-metaboli zing, variant forms. We tested the hypothesis that the slow alleles of thes e enzymes can modify the inverse association between NSAIDs and colon neopl asia in the Minnesota Cancer Prevention Research Unit (CPRU) adenomatous po lyp case-control study. CYP2C9 and UGT1A6 genotypes were determined for 474 adenoma cases and 563 controls. NSAID use was inversely associated with ad enoma risk [odds ratio (OR), 0.63; 95% confidence interval (CI), 0.44-0.90 for aspirin; and OR, 0.50; 95% CI, 0.31-0.82 for nonaspirin NSAID]. However , this association was absent in aspirin users who carried the CYP2C9 varia nt alleles (OR, 0.88; 95% CI, 0.51-1.53) or who were homozygous wild-type U GT1A6 (OR, 0.86; 95% CI, 0.50-1.50). Carriers of both of these alleles who use aspirin were also not at reduced risk of adenomatous polyps (OR, 1.59; 95% CI, 0.68-3.73). The variants of these enzymes did not influence the ass ociation between nonaspirin NSAIDs and adenoma risk. These data indicate th at the effectiveness of chemopreventive drugs can be modulated by the genot ype of metabolizing enzymes.