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

Abstract

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-me-diated 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.Onthe 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> Ton SN-38 glucuronidation is attributable to its close association with either UGT1A1*6,*28,or*60. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.