Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer
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The phenotypic effects of UGT1A7 and UGT1A9 genetic polymorphisms on the in vivo pharmacokinetics of irinotecan were examined.
Eighty-four Japanese patients with cancer who received irinotecan-based chemotherapy were enrolled. Polymorphisms present in UGT1A7 (T to G transversion at −57 and UGT1A7*2 to *9), UGT1A9 (9 or 10 repeat of T at −118 [−118(T)9 or 10] and UGT1A9*2 to *5), and UGT1A1 (UGT1A1*6, UGT1A1*27, and UGT1A1*28) were analyzed for all patients. Pharmacokinetics of irinotecan were examined in 52 patients.
The most frequent haplotype (haplotype I, 56.7%, 95% CI 53.1–60.4) consisted of polymorphisms related to normal catalytic or transcriptional activity [T at −57 and *1 of UGT1A7, −118(T)10 of UGT1A9, and UGT1A1*1]. The second most frequent haplotype (haplotype II, 15.0%, 95% CI 12.4–18.3) consisted of polymorphisms related to reduced catalytic or transcriptional activity [−57T > G and *3 of UGT1A7 and −118(T)9 of UGT1A9 linked to UGT1A1*6]. The AUCSN-38/AUCSN-38G ratios in three patients homozygous for haplotype II were significantly higher than those in 20 patients with I/I diplotype (P = 0.011). Neither of these patients had UGT1A1*28.
Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6, related to reduced catalytic and transcriptional activities of UGTs, is associated with the decreased glucuronosyltransferase activity for SN-38 in Japanese patients with cancer.
KeywordsIrinotecan SN-38 Polymorphism UGT1A7 UGT1A9 UGT1A1*6
- 1.Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ (1998) Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847–854PubMedGoogle Scholar
- 4.Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388PubMedCrossRefGoogle Scholar
- 14.Villeneuve L, Girard H, Fortier LC, Gagne JF, Guillemette C (2003) Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and African-American subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs. J Pharmacol Exp Ther 307:117–128PubMedCrossRefGoogle Scholar
- 15.Jinno H, Saeki M, Saito Y, Tanaka-Kagawa T, Hanioka N, Sai K, Kaniwa N, Ando M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Ozawa S, Sawada J (2003) Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients. J Pharmacol Exp Ther 306:688–693PubMedCrossRefGoogle Scholar
- 20.Saeki M, Saito Y, Jinno H, Sai K, Ozawa S, Kurose K, Kaniwa N, Komamura K, Kotake T, Morishita H, Kamakura S, Kitakaze M, Tomoike H, Shirao K, Tamura T, Yamamoto N, Kunitoh H, Hamaguchi T, Yoshida T, Kubota K, Ohtsu A, Muto M, Minami H, Saijo N, Kamatani N, Sawada JI (2006) Haplotype structures of the UGT1A gene complex in a Japanese population. Pharmacogenomics J 6:63–75PubMedCrossRefGoogle Scholar
- 22.Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H, Hasegawa R, Kaniwa N, Sawada J, Komamura K, Ueno K, Kamakura S, Kitakaze M, Kitamura Y, Kamatani N, Minami H, Ohtsu A, Shirao K, Yoshida T, Saijo N (2004) UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther 75:501–515PubMedCrossRefGoogle Scholar
- 24.Girard H, Court MH, Bernard O, Fortier LC, Villeneuve L, Hao Q, Greenblatt DJ, von Moltke LL, Perussed L, Guillemette C (2004) Identification of common polymorphisms in the promoter of the UGT1A9 gene: evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver. Pharmacogenetics 14:501–515PubMedCrossRefGoogle Scholar
- 27.Akaba K, Kimura T, Sasaki A, Tanabe S, Ikegami T, Hashimoto M, Umeda H, Yoshida H, Umetsu K, Chiba H, Yuasa I, Hayasaka K (1998) Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. Biochem Mol Biol Int 46:21–26PubMedGoogle Scholar
- 30.Han JY, Lim HS, Shin ES, Yoo YK, Park YH, Lee JE, Jang IJ, Lee DH, Lee JS (2006) Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 24:2237–2244PubMedCrossRefGoogle Scholar