Samowitz Wade S, Wolff Roger K, Curtin Karen, Sweeney Carol, Ma Khe-Ni, Andersen Kristen, Levin Theodore R, Slattery Martha L
Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
Clin Gastroenterol Hepatol. 2006 Jul;4(7):894-901. doi: 10.1016/j.cgh.2006.04.021. Epub 2006 Jun 22.
Variant genotypes of uridine diphosphate glucuronsyltransferase isoenzyme 1A6 (UGT1A6) associated with decreased metabolic activity have been associated with an enhanced protective effect of aspirin on the development of colorectal adenomas. However, interactions between UGT1A6 variants or variants of another enzyme that metabolizes nonsteroidal anti-inflammatory drugs (NSAIDs), cytochrome P4502C9 (CYP2C9), and NSAIDs in the prevention of colorectal cancer have not been studied extensively.
UGT1A6 and CYP2C9 genotypes were determined in 2295 individuals with colorectal cancer and 2903 controls. Interactions between these genotypes, aspirin or ibuprofen use, and colorectal cancer risk were determined.
Variant CYP2C9 genotypes enhanced the protective effect of ibuprofen on the prevention of colorectal cancer, and a dose-response relationship with respect to increasing numbers of variant alleles was seen (P interaction = .02). CYP2C9 variants were more effective in individuals with wild-type rather than variant UGT1A6 (P interaction < .007). Variant CYP2C9 genotypes showed no interaction with aspirin usage, and variant UGT1A6 genotypes showed no interaction with either NSAID with respect to colorectal cancer protection.
In this study, the major effect seen was an enhancement by slower-metabolizing CYP2C9 variants of the chemopreventive activity of ibuprofen against colorectal cancer.
尿苷二磷酸葡萄糖醛酸基转移酶同工酶1A6（UGT1A6）的变异基因型与代谢活性降低相关，且与阿司匹林对结肠直肠腺瘤发生的增强保护作用有关。然而，UGT1A6变异体之间或另一种代谢非甾体抗炎药（NSAIDs）的酶——细胞色素P4502C9（CYP2C9）的变异体与NSAIDs在预防结直肠癌方面的相互作用尚未得到广泛研究。
对2295例结直肠癌患者和2903例对照者进行UGT1A6和CYP2C9基因型测定。确定这些基因型、阿司匹林或布洛芬使用与结直肠癌风险之间的相互作用。
CYP2C9变异基因型增强了布洛芬对结直肠癌的预防保护作用，且观察到与变异等位基因数量增加存在剂量反应关系（P相互作用 = 0.02）。CYP2C9变异体在野生型而非变异型UGT1A6个体中更有效（P相互作用 < 0.007）。CYP2C9变异基因型与阿司匹林使用无相互作用，UGT1A6变异基因型在结直肠癌保护方面与任何一种NSAIDs均无相互作用。
在本研究中，主要发现是代谢较慢的CYP2C9变异体增强了布洛芬对结直肠癌的化学预防活性。
