Effects of polymorphic cytochrome P450 2A6 genotypes on chemoprevention against colorectal tumors in single Japanese cohort using daily low-dose aspirin: insights into future personalized treatments

Journal of Pharmaceutical Health Care and Sciences

Hideki Ishikawa¹  Sadao Suzuki²  Takahiro Otani²  Kanae Mure³  Ami Mizugaki⁴  Makiko Shimizu⁴  Hiroshi Yamazaki⁴ 

[1] Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto, Japan;Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan;Department of Public Health, Wakayama Medical University School of Medicine, Wakayama, Japan;Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, 194-8543, Tokyo, Japan;

关键词: CYP2A6;    Acetylsalicylic acid;    Chemoprevention;    Ethnic difference;   

DOI  :  10.1186/s40780-021-00209-8

来源: Springer

【 摘 要 】

BackgroundA chemopreventive effect of low-dose aspirin against colorectal tumors was previously found in participants of two Japanese multicenter, double-blind, randomized, placebo-controlled clinical trials investigating the effects of daily aspirin (100 mg/day) for 0.7–2 years on tumor recurrence in colorectal cancer patients whose tumors were excised endoscopically.MethodsIn the current study, chemopreventive data from single-center subsets having daily aspirin (100 mg/day) were reanalyzed with respect to variations in polymorphic cytochrome P450 2A6 (CYP2A6). From the J-CAPP study, 56 of 311 participants (47 men, 9 women; excluding patients with familial adenomatous polyposis) were genotyped for CYP2A6*1, *4 (whole-gene deletion), *7 (amino acid substitution), and *9 (upstream mutation), and from the J-FAPP IV study, 81 of 102 participants (43 men, 38 women; including patients with familial adenomatous polyposis) were also genotyped.ResultsThe chemopreventive effects of daily aspirin were found to be inversely dependent on the predicted enzyme activity of the CYP2A6 phenotype [based on normal genotypes (CYP2A6*1/*1,*7,*9) and impaired genotypes (CYP2A6*4,*7,*9/*4,*7,*9 and CYP2A6*1/*4)] among a nonsmoker Japanese cohort without familial adenomatous polyposis.ConclusionsThe CYP2A6 wild-type allele could be a candidate biomarker for reduced chemopreventive effects of daily aspirin in a population with wide-ranging CYP2A6 phenotypes with a high frequency of impaired activities resulting from variations and whole-gene deletions. The CYP2A6 genotypes could be applicable to future personalized treatments for colorectal tumor chemoprevention with daily aspirin.

【 授权许可】

CC BY