Time-Dependent Metabolism of Luteolin by Human UDP-Glucuronosyltransferases and Its Intestinal First-Pass Glucuronidation in Mice
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- 作者：Lili Wu ; Junjin Liu ; Weichao Han ; Xuefeng Zhou ; Xiaoming Yu ; Qiang Wei ; Shuwen Liu ; Lan Tang
- 刊名：Journal of Agricultural and Food Chemistry
- 出版年：2015
- 出版时间：October 7, 2015
- 年：2015
- 卷：63
- 期：39
- 页码：8722-8733
- 全文大小：835K
- ISSN：1520-5118
文摘
Luteolin is a well-known flavonoid with various pharmacological properties but has low bioavailability due to glucuronidation. This study investigated the time-course of luteolin glucuronidation by 12 human UDP-glucuronosyltransferases (UGTs) and its intestinal first-pass metabolism in mice. Six metabolites, including two novel abundant diglucuronides [3鈥?7-O-diglucuronide (diG) and 4鈥?7-diG] and four known ones, were identified. UGT1A6 and UGT1A9 generated almost only monoglucuronides (G鈥檚). The production of 3鈥?7-diG followed a sequential time-dependent process along with decrease of 3鈥?G mainly by UGT1A1, indicating that 3鈥?7-diG was produced from 3鈥?G. Metabolism in mice intestine differed from that in humans. Probenecid, a nonspecific UGT inhibitor, did not affect absorption but significantly inhibited production of 7-, 4鈥?, and 3鈥?G, and enhanced the formation of another novel metabolite, 5-G, in mice. In conclusion, diglucuronide formation is time-dependent and isoform-specific. UGT1A1 preferentially generates diG, whereas UGT1A6 and UGT1A9 share a preference for G production.