title: Tissue and species differences in the glucuronidation of glabridin with UDP-glucuronosyltransferases.
abstract: Glabridin (GA) has gained wide application in the cosmetics and food industry. This study was performed to investigate its metabolic inactivation and elimination by glucuronidation by use of liver and intestine microsomes from humans (HLM and HIM) and rats (RLM and RIM), and liver microsomes from cynomolgus monkeys and beagle dogs (CyLM and DLM). Both hydroxyl groups at the C2 and C4 positions of the B ring are conjugated to generate two mono-glucuronides (M1 and M2). HIM, RIM and RLM showed the most robust activity in catalyzing M2 formation with intrinsic clearance values (Clint) above 2000 μL/min/mg, with little measurable M1 formation activity. DLM displayed considerable activity both in M1 and M2 formation, with Clint values of 71 and 214 μL/min/mg, respectively, while HLM and CyLM exhibited low activities in catalyzing M1 and M2 formation, with Clint values all below 20 μL/min/mg. It is revealed that UGT1A1, 1A3, 1A9, 2B7, 2B15 and extrahepatic UGT1A8 and 1A10 are involved in GA glucuronidation. Nearly all UGTs preferred M2 formation except for UGT1A1. Notably, UGT1A8 displayed the highest activity with a Clint value more than 5-fold higher than the other isoforms. Chemical inhibition studies, using selective inhibitors of UGT1A1, 1A9, 2B7 and 1A8, further revealed that UGT1A8 contributed significantly to intestinal GA glucuronidation in humans. In summary, this in vitro study demonstrated large species differences in GA glucuronidation by liver and intestinal microsomes, and that intestinal UGTs are important for the pathway in humans.
authors.affiliation: The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, Dalian, China. Electronic address: binguo_ln@163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, China; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, Dalian, China.
authors.forename: Zhongze
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, Dalian, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: The Centre for Drug and Food Safety Evaluation, School of Life Science, Anqing Normal University, Anqing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Yangliu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: The Centre for Drug and Food Safety Evaluation, School of Life Science, Anqing Normal University, Anqing, China. Electronic address: zhull_better@163.com.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, Dalian, China; Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Guangbo
authors.initials: G
authors.lastname: Ge
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Sun
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D004285:Dogs; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007529:Isoflavones / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism*; D008875:Middle Aged; D010636:Phenols / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D055815:Young Adult
chemical_list: D020719:Glucuronides; D007529:Isoflavones; D010636:Phenols; D014453:Glucuronosyltransferase; C454320:UDP-glucuronosyltransferase, UGT1A8; C107601:glabridin
keywords: Glabridin; Glucuronidation; Species differences; UDP-glucuronosyltransferases