Bigler J, Whitton J, Lampe J W, Fosdick L, Bostick R M, Potter J D
Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Cancer Res. 2001 May 1;61(9):3566-9.
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.
经常使用非甾体抗炎药（NSAIDs）对结肠肿瘤的发生率具有保护作用。然而，NSAIDs代谢酶的基因多态性可能会改变这种作用。NSAIDs，尤其是阿司匹林，可被尿苷二磷酸葡萄糖醛酸基转移酶1A6（UGT1A6）进行葡萄糖醛酸化，并且某些种类的NSAIDs也可被细胞色素P450（CYP）2C9代谢。这两种酶均具有代谢缓慢的变异形式。在明尼苏达癌症预防研究单位（CPRU）腺瘤性息肉病例对照研究中，我们检验了这样一个假设，即这些酶的慢代谢等位基因可改变NSAIDs与结肠肿瘤之间的负相关关系。对474例腺瘤病例和563例对照测定了CYP2C9和UGT1A6基因型。使用NSAIDs与腺瘤风险呈负相关[比值比（OR），0.63；95%置信区间（CI），阿司匹林为0.44 - 0.90；非阿司匹林NSAIDs的OR为0.50；95%CI，0.31 - 0.82]。然而，携带CYP2C9变异等位基因的阿司匹林使用者（OR，0.88；95%CI，0.51 - 1.53）或UGT1A6纯合野生型的阿司匹林使用者（OR，0.86；95%CI，0.50 - 1.50）中不存在这种相关性。同时携带这两种等位基因且使用阿司匹林的个体患腺瘤性息肉的风险也未降低（OR，1.59；95%CI，0.68 - 3.73）。这些酶的变异并未影响非阿司匹林NSAIDs与腺瘤风险之间关联。这些数据表明，化学预防药物的有效性可被代谢酶的基因型所调节。
