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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional Characterization of Human UDP-Glucuronosyltransferase 1A9 Variant, D256N, Found in Japanese Cancer Patients

Project Team for Pharmacogenetics (H.J., M.S., Y.S., N.H., K.Sa., N.K., S.O., J.S.), Division of Environmental Chemistry (H.J., T.T.-K., N.H., M.A.), Division of Biochemistry and Immunochemistry (Y.S., J.S.), Division of Xenobiotic Metabolism and Disposition (K.Sa.), Division of Medicinal Safety Science (N.K.), and Division of Pharmacology (S.O.), National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo, Japan; Gastrointestinal Oncology Division (K.Sh.), Medical Oncology Division (N.S.), National Cancer Center Hospital, Genetics Division (T.Y.), National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan; and Division of Oncology/Hematology (H.M.), Division of Gastrointestinal Oncology/Digestive Endoscopy (A.O.), National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, Japan

SN-38 (7-ethyl-10-hydroxycamptothecin), an active metabolite of the antitumor prodrug irinotecan, is conjugated and detoxified to SN-38 10-O--D-glucuronide by hepatic UDP-glucuronosyltransferase (UGT) 1A1. Recent studies have revealed that other UGT1A isoforms, UGT1A7 and UGT1A9, also participate in SN-38 glucuronidation. Although several genetic polymorphisms are reported for UGT1A1 and UGT1A7 that affect the SN-38 glucuronidation activities, no such polymorphisms have been identified for UGT1A9. In the present study, UGT1A9 exon 1 and its flanking regions were sequenced from 61 Japanese cancer patients who were all treated with irinotecan. A novel nonsynonymous single nucleotide polymorphism was identified in UGT1A9 exon 1, heterozygous 766G>A resulting in the amino acid substitution of D256N. The wild-type and D256N UGT1A9s were transiently expressed at similar protein levels in COS-1 cells, and their membrane fractions were characterized in vitro for the glucuronidation activities toward SN-38. The apparent K_m values were 19.3 and 44.4 µM, and the V_max values were 2.94 and 0.24 pmol/min/mg of membrane protein for the wild-type and D256N variant, respectively. The SN-38 glucuronidation efficiency (normalized V_max/K_m) of D256N was less than 5% that of wild-type UGT1A9. These results clearly indicate that the D256N variant is essentially nonfunctional with regard to SN-38 glucuronidation. These findings highlight the importance of further studies into the potential influence of UGT1A9 D256N variant to irinotecan metabolism in vivo.

Address correspondence to: Dr. Nobumitsu Hanioka, Division of Environmental Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. E-mail: hanioka{at}nihs.go.jp

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