机构：[1]Department of Pharmacy, First Hospital Affiliated to Shihezi University, Shihezi, Xinjiang, 832002, China,[2]International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
This study aimed to determine the reaction kinetics of the regioselective glucuronidation of diosmetin and chrysoeriol, two important methylated metabolites of luteolin, by human liver microsomes (HLMs) and uridine-5'-diphosphate glucuronosyltransferase (UGTs) enzymes. This study also investigated the effects of breast cancer resistance protein (BCRP) on the efflux of diosmetin and chrysoeriol glucuronides in HeLa cells overexpressing UGT1A9 (HeLa-UGT1A9). After incubation with HLMs in the presence of UDP-glucuronic acid, diosmetin and chrysoeriol gained two glucuronides each, and the OH-in each B ring of diosmetin and chrysoeriol was the preferable site for glucuronidation. Screening assays with 12 human expressed UGT enzymes and chemical-inhibition assays demonstrated that glucuronide formation was almost exclusively catalyzed by UGT1A1, UGT1A6, and UGT1A9. Importantly, in HeLa-UGT1A9, Ko143 significantly inhibited the efflux of diosmetin and chrysoeriol glucuronides and increased their intracellular levels in a dose-dependent manner. This observation suggested that BCRP-mediated excretion was the predominant pathway for diosmetin and chrysoeriol disposition. In conclusion, UGT1A1, UGT1A6, and UGT1A9 were the chief contributors to the regioselective glucuronidation of diosmetin and chrysoeriol in the liver. Moreover, cellular glucuronidation was significantly altered by inhibiting BCRP, revealing a notable interplay between glucuronidation and efflux transport. Diosmetin and chrysoeriol possibly have different effects on anti-cancer due to the difference of UGT isoforms in different cancer cells.
基金：
This research was supported by the joint
fund set up by the National Natural Science
Foundation of China (No. U1203204), the National
Natural Science Foundation of China (No.
81460638, 81360671), Science and Technology
Project of Guangzhou City (201509010004) and
Guangdong Natural Science Foundation Province
(2015AD030312012).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2015]版：
大类|3 区生物
小类|3 区综合性期刊
最新[2025]版：
大类|3 区综合性期刊
小类|3 区综合性期刊
第一作者：
第一作者机构：[1]Department of Pharmacy, First Hospital Affiliated to Shihezi University, Shihezi, Xinjiang, 832002, China,[2]International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Xuejun Zeng,Jian Shi,Min Zhao,et al.Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells.[J].PloS one.2016,11(11):e0166239.doi:10.1371/journal.pone.0166239.
APA：
Xuejun Zeng,Jian Shi,Min Zhao,Qingwei Chen,Liping Wang...&Zhongqiu Liu.(2016).Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells..PloS one,11,(11)
MLA：
Xuejun Zeng,et al."Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells.".PloS one 11..11(2016):e0166239
