Metabolic Profile, Enzyme Kinetics, and Reaction Phenotyping of 尾-Lapachone Metabolism in Human Liver and Intestine in Vitro
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- 作者：Xuefang Cheng ; Fang Liu ; Tingting Yan ; Xueyan Zhou ; Liang Wu ; Ke Liao ; Guangji Wang ; Haiping Hao
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：December 3, 2012
- 年：2012
- 卷：9
- 期：12
- 页码：3476-3485
- 全文大小：432K
- 年卷期：v.9,no.12(December 3, 2012)
- ISSN：1543-8392
文摘
尾-Lapachone (尾-Lap) is an NAD(P)H:quinone oxidoreductase 1 (NQO1) target antitumor drug candidate in phase II clinical trials. The present study aimed to uncover the metabolic profile, enzyme kinetics, and enzyme isoforms for the metabolism of 尾-Lap in human liver and intestine in vitro. NQO1-mediated quinone reduction and subsequent glucuronidation is the predominant metabolic pathway for 尾-Lap in humans; a pair of regioisomers (M1 and M2) of reduced 尾-Lap glucuronides were the major metabolites found from human S9 incubations. The overall glucuronidation clearance of 尾-Lap in human liver S9 was 4754.90 渭L/min/mg of protein and was 8.1-fold of that in human intestinal S9. Recombinant UDP-glucuronosyltransferase (UGT) screening, correlation analysis, enzyme kinetics, and chemical inhibition study were performed to determine the UGT isoforms involved in 尾-Lap metabolism. UGT1A7, UGT1A8, and UGT1A9 are the predominant isoforms responsible for the formation of M2 while UGT2B7 is the main isoform for M1, suggesting a regioselective glucuronidation of reduced quinone by UGTs. It was of interest to find that 尾-Lap underwent nonenzymatic two-electron reduction, providing a novel explanation for the toxicities of 尾-Lap to NQO1-negative cells at high concentration and with long-time incubation. In conclusion, this study contributes to a better understanding of not only 尾-Lap metabolism but its antitumor property as well.