title: Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity.
abstract: Genetic polymorphism of the UDP-glucuronosyltransferase (UGT) 1A1 gene is associated with the decreased glucuronidation activity of an active metabolite of irinotecan, SN-38, and UGT1A1*28 has been shown as a predictive factor for irinotecan toxicity. The phenobarbital-responsive enhancer module (PBREM) of the UGT1A1 promoter region has been reportedly associated with the transcriptional activity of the gene. We investigated whether the polymorphism of PBREM (T-3279G) would affect inter-patient variations in sensitivity to irinotecan toxicity. The study population comprised 119 cancer patients who had received irinotecan. We reviewed their clinical records, including patient characteristics, and observed their toxicity levels following irinotecan infusion. Genotyping was performed by sequencing analyses. Logistic regression analyses were performed to assess the relationship between genotypes and irinotecan toxicity. We identified the homozygotes of the reference allele for T-3279G in 68 patients, the heterozygotes in 37, and the homozygotes for the variant in 14. Logistic regression analysis indicated a significant association between the homozygotes for T-3279G and the severe toxicity (odds ratio 5.80; 95% confidence interval 1.67-20.1). However, multivariate analysis, including the data of UGT1A1*28 polymorphism, revealed a diminution of the association due to a highly significant linkage disequilibrium between these polymorphisms. Our results suggest that a highly significant linkage disequilibrium exists between T-3279G and UGT1A1*28 polymorphisms, and that the variants of T-3279G and UGT1A1*28 cooperatively decrease transcriptional activity of the UGT1A1 promoter. The determination of T-3279G and UGT1A1*28 genotypes might be clinically useful in predicting severe irinotecan toxicity in cancer patients.
authors.affiliation: Department of Medicine, Division of Respiratory Diseases, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Chiyoe
authors.initials: C
authors.lastname: Kitagawa
authors.forename: Maki
authors.initials: M
authors.lastname: Ando
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shimokata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity*; D004742:Enhancer Elements, Genetic; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D000077146:Irinotecan; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D010634:Phenobarbital / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012306:Risk; D013997:Time Factors; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D018691:Excitatory Amino Acid Antagonists; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D010634:Phenobarbital; D000099148:UGT1A1 Enzyme