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Vol. 62, Issue 3, 608-617, September 2002
Faculty of Pharmacy (J.-F.G., V.M., K.J., G.G., C.G.),
Oncology and Molecular Endocrinology Research Center (J.-F.G., V.M.,
K.J., P.B., C.G.) CHUL Research Center (CHUQ), Laval University,
Quebec, Canada
7-Ethyl-10-hydroxycamptothecin (SN-38) is the pharmacologically active
metabolite of irinotecan, in addition to being responsible for severe
toxicity. Glucuronidation is the main metabolic pathway of SN-38 and
has been shown to protect against irinotecan-induced gastrointestinal
toxicity. The purpose of this study was to determine whether common
polymorphic UDP-glucuronosyltransferase (UGT) affects SN-38
glucuronidation. First, kinetic characterization of SN-38-glucuronide (SN-38-G) formation was assessed for all known human UGT1A and UGT2B
overexpressed in human embryonic kidney 293 cells. To assess the
relative activity of UGT isoenzymes for SN-38, rates of formation of
SN-38-G were monitored by liquid chromatography/mass spectrometry analysis and normalized by level of UGT cellular expression.
Determination of intrinsic clearances predicts that hepatic UGT1A1 and
UGT1A9 and the extrahepatic UGT1A7 are major components in SN-38-G
formation, whereas a minor role is suggested for UGT1A6, UGT1A8, and
UGT1A10. In support of the involvement of UGT1A9, a strong coefficient of correlation was observed in the glucuronidation of SN-38 and a
substrate, mainly glucuronidate, by UGT1A9 (flavopiridol) by human
liver microsomes (coefficient of correlation, 0.905;
p = 0.002). In vitro functional experiments
revealed a negative impact of the UGT1A1 allelic variants. Residual
activities of 49, 7, 8, and 11% were observed for UGT1A1*6
(G71R), UGT1A1*27 (P229Q), UGT1A1*35
(L233R), and UGT1A1*7 (Y486D), respectively.
Common variants of UGT1A7, UGT1A7*3
(N129K;R131K;W208R), and UGT1A7*4
(W208R), displayed residual activities of 41 and 28%
compared with the UGT1A7*1 allele. Taken together, these data provide
the evidence that molecular determinants of irinotecan response may
include the UGT1A polymorphisms studied herein and
common genetic variants of the hepatic UGT1A9 isoenzyme yet to be described.
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