%0 Journal Article
%A Yoshiro Saito
%A Kimie Sai
%A Keiko Maekawa
%A Nahoko Kaniwa
%A Kuniaki Shirao
%A Tetsuya Hamaguchi
%A Noboru Yamamoto
%A Hideo Kunitoh
%A Yuichiro Ohe
%A Yasuhide Yamada
%A Tomohide Tamura
%A Teruhiko Yoshida
%A Hironobu Minami
%A Atsushi Ohtsu
%A Yasuhiro Matsumura
%A Nagahiro Saijo
%A Jun-ichi Sawada
%T Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese
%D 2009
%R 10.1124/dmd.108.024208
%J Drug Metabolism and Disposition
%P 272-276
%V 37
%N 2
%X The anticancer prodrug, irinotecan, is converted to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterases, and SN-38 is inactivated by UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation. UGT1A9 also mediates this reaction. In a recent study, it was reported that the UGT1A9 IVS1+399 (I399)C>T polymorphism is associated with increased SN-38 glucuronidation both in vitro and in vivo. However, its role in UGT1A9 expression levels and activity is controversial. Thus, we evaluated the role of I399C>T in SN-38 glucuronidation using 177 Japanese cancer patients administered irinotecan. I399C>T was detected at a 0.636 allele frequency. This polymorphism was in strong linkage disequilibrium (LD) with UGT1A9*1b (–126_–118T9>T10, |D′| = 0.99) and UGT1A1*6 (211G>A, 0.86), in moderate LD with UGT1A1*60 (–3279T>G, 0.55), but weakly associated with UGT1A1*28 (–54_–39A(TA)6TAA>A(TA)7TAA, 0.25). Haplotype analysis showed that 98% of the I399C alleles were linked with low-activity haplotypes, either UGT1A1*6, *28, or *60. On the other hand, 85% of the T alleles were linked with the UGT1A1 wild-type haplotype *1. Although I399T-dependent increases in SN-38 glucuronide/SN-38 area under concentration-time curve (AUC) ratio (an in vivo marker for UGT1A activity) and decreases in SN-38 AUC/dose were apparent (P < 0.0001), these effects were no longer observed after stratified patients by UGT1A1*6, *28, or *60 haplotype. Thus, at least in Japanese populations, influence of I399C>T on SN-38 glucuronidation is attributable to its close association with either UGT1A1*6, *28, or *60. The American Society for Pharmacology and Experimental Therapeutics
%U https://dmd.aspetjournals.org/content/dmd/37/2/272.full.pdf