title: CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk.
abstract: Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has a protective effect on the incidence of colon neoplasia. However, polymorphisms in NSAID-metabolizing enzymes may alter this effect. NSAIDs, particularly aspirin, are glucuronidated by UGT1A6 and some classes of NSAIDs are also metabolized by cytochrome P450 (CYP) 2C9. Both of these enzymes have slow-metabolizing, variant forms. We tested the hypothesis that the slow alleles of these enzymes can modify the inverse association between NSAIDs and colon neoplasia in the Minnesota Cancer Prevention Research Unit (CPRU) adenomatous polyp case-control study. CYP2C9 and UGT1A6 genotypes were determined for 474 adenoma cases and 563 controls. NSAID use was inversely associated with adenoma 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 variant alleles (OR, 0.88; 95% CI, 0.51-1.53) or who were homozygous wild-type UGT1A6 (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 association between nonaspirin NSAIDs and adenoma risk. These data indicate that the effectiveness of chemopreventive drugs can be modulated by the genotype of metabolizing enzymes.
authors.affiliation: Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. jbigler@fhcrc.org
authors.forename: J
authors.initials: J
authors.lastname: Bigler
authors.forename: J
authors.initials: J
authors.lastname: Whitton
authors.forename: J W
authors.initials: JW
authors.lastname: Lampe
authors.forename: L
authors.initials: L
authors.lastname: Fosdick
authors.forename: R M
authors.initials: RM
authors.lastname: Bostick
authors.forename: J D
authors.initials: JD
authors.lastname: Potter
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D018256:Adenomatous Polyps / Q000201:enzymology / Q000235:genetics; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases; D001241:Aspirin / Q000627:therapeutic use*; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; D001241:Aspirin