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Vol. 31, Issue 1, 108-113, January 2003

Glucuronidation of 7-Ethyl-10-hydroxycamptothecin (SN-38), an Active Metabolite of Irinotecan (CPT-11), by Human UGT1A1 Variants, G71R, P229Q, and Y486D

Hideto Jinno, Toshiko Tanaka-Kagawa, Nobumitsu Hanioka, Mayumi Saeki, Seiichi Ishida, Tetsuji Nishimura, Masanori Ando, Yoshiro Saito, Shogo Ozawa, and Jun-ichi Sawada

Project Team for Pharmacogenetics (N.H., M.S., S.I, Y.S., S.O., J.S.), Division of Environmental Chemistry (H.J., T.T.-K., N.H., T.N., M.A.), Division of Biochemistry and Immunochemistry (Y.S., J.S.), and Division of Pharmacology (S.I., S.O.), National Institute of Health Sciences, Tokyo, Japan

7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of antitumor agent irinotecan (CPT-11), is conjugated and detoxified to SN-38-glucuronide by UDP-glucuronosyltransferase (UGT) 1A1. Genetic polymorphisms in UGT1A1 are thought to contribute to severe diarrhea and/or leukopenia caused by CPT-11. In this regard, it has been reported that polymorphisms in the promoter region could affect the CPT-11 pharmacokinetics and interindividual variation of toxicity. However, little information is available on the influence of UGT1A1 polymorphisms in the coding region on the SN-38 glucuronidation activity. In the present study, wild-type (WT) and three variant (G71R, P229Q, and Y486D) cDNAs of human UGT1A1s were transiently expressed in COS-1 cells, and the kinetic parameters of these UGT1A1s were determined for SN-38 glucuronidation. A partially reduced UGT1A1 protein expression was observed in COS-1 cells for G71R and Y486D. WT UGT1A1 catalyzed SN-38 glucuronidation with an apparent Km value of 11.5 µM, whereas those of G71R, P229Q, and Y486D were 14.0, 18.0, and 63.5 µM, respectively. The SN-38 glucuronidation efficiency ratio (Vmax/Km) normalized for the level of expression was 1.4, 0.66 (47% of WT), 0.73 (52%), and 0.07 (5%) µl/min/mg of protein for WT, G71R, P229Q, and Y486D, respectively. Thus, the SN-38 glucuronidation activity of Y486D was drastically reduced, whereas the reduction in the G71R and P229Q activities was fractional. The decreased SN-38 glucuronidation efficiency ratio of G71R and P229Q could be critical in combination with other polymorphisms in the UGT1A1 gene.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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