title: Time-Dependent Metabolism of Luteolin by Human UDP-Glucuronosyltransferases and Its Intestinal First-Pass Glucuronidation in Mice.
abstract: 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',7-O-diglucuronide (diG) and 4',7-diG] and four known ones, were identified. UGT1A6 and UGT1A9 generated almost only monoglucuronides (G's). The production of 3',7-diG followed a sequential time-dependent process along with decrease of 3'-G mainly by UGT1A1, indicating that 3',7-diG was produced from 3'-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'-, and 3'-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.
authors.affiliation: Guangdong Provincial Key Labortory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wu
authors.affiliation: Guangdong Provincial Key Labortory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
authors.forename: Junjin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Labortory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
authors.forename: Weichao
authors.initials: W
authors.lastname: Han
authors.affiliation: Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences , Guangzhou 510301, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Urology, Nanfang Hospital, Southern Medical University , Guangzhou 510515, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Urology, Nanfang Hospital, Southern Medical University , Guangzhou 510515, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Guangdong Provincial Key Labortory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.|State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University , Guangzhou 510515, China.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Labortory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.|State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University , Guangzhou 510515, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
mesh_terms: D000818:Animals; D001682:Biological Availability; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000737:chemistry; D007700:Kinetics; D047311:Luteolin / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice
chemical_list: D020719:Glucuronides; D014453:Glucuronosyltransferase; D047311:Luteolin
keywords: UGTs; absorption; diglucuronidation; luteolin; metabolism; time-dependent