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SHORT COMMUNICATION

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

Project Team for Pharmacogenetics (Y.S., K.Sa., K.M., N.K., J.S.), Division of Functional Biochemistry and Genomics (Y.S., K.Sa., K.M., J.S.), Division of Medicinal Safety Science (N.K.), National Institute of Health Sciences, Tokyo, Japan; Gastrointestinal Oncology Division (K.Sh., T.H., Y.Y.), Thoracic Oncology Division (N.Y., H.K., Y.O., T.T.), National Cancer Center Hospital, Genetics Division (T.Y.), National Cancer Center Research Institute, National Cancer Center, Tokyo, Japan; Division of Oncology/Hematology (H.M.), Division of Gastrointestinal Oncology/Digestive Endoscopy (A.O.), Investigative Treatment Division, Research Center for Innovative Oncology (Y.M.), Deputy Director (N.S.), National Cancer Center Hospital East, Kashiwa, Japan

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.