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Int. J. Mol. Sci. 2017, 18(9), 1983; doi:10.3390/ijms18091983

In Vitro Glucuronidation of Wushanicaritin by Liver Microsomes, Intestine Microsomes and Expressed Human UDP-Glucuronosyltransferase Enzymes

1,2,3,†
,
1,2,†
,
1,2,4,* , 1,2
,
1,2
,
1,2,3
,
1,2,* , 5
and
1,2,3,4
1
College of Pharmacy, Jinan University, Guangzhou 510632, China
2
Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
3
Guangzhou Research and Creativity Biotechnology Co., Ltd., Guangzhou 510663, China
4
Integrated Chinese and Western Medicine Postdoctoral research station, Jinan University, Guangzhou 510632, China
5
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 13 August 2017 / Revised: 5 September 2017 / Accepted: 14 September 2017 / Published: 19 September 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Wushanicaritin, a natural polyphenol compound, exerts many biological activities. This study aimed to characterize wushanicaritin glucuronidation by pooled human liver microsomes (HLM), human intestine microsomes and individual uridine diphosphate-glucuronosyltransferase (UGT) enzyme. Glucuronidation rates were determined by incubating wushanicaritin with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Reaction phenotyping, the relative activity factor (RAF) and activity correlation analysis were performed to identify the main UGT isoforms. Wushanicaritin glucuronidation in HLM was efficient with a high CLint (intrinsic clearance) value of 1.25 and 0.69 mL/min/mg for G1 and G2, respectively. UGT1A1 and 1A7 showed the highest activities with the intrinsic clearance (CLint) values of 1.16 and 0.38 mL/min/mg for G1 and G2, respectively. In addition, G1 was significantly correlated with β-estradiol glucuronidation (r = 0.847; p = 0.0005), while G2 was also correlated with chenodeoxycholic acid glucuronidation (r = 0.638, p = 0.026) in a bank of individual HLMs (n = 12). Based on the RAF approach, UGT1A1 contributed 51.2% for G1, and UGT1A3 contributed 26.0% for G2 in HLM. Moreover, glucuronidation of wushanicaritin by liver microsomes showed marked species difference. Taken together, UGT1A1, 1A3, 1A7, 1A8, 1A9 and 2B7 were identified as the main UGT contributors responsible for wushanicaritin glucuronidation. View Full-Text
Keywords: wushanicaritin; glucuronidation; UDP-glucuronosyltransferase; activity correlation analysis; relative activity factor; species difference wushanicaritin; glucuronidation; UDP-glucuronosyltransferase; activity correlation analysis; relative activity factor; species difference
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MDPI and ACS Style

Hong, X.; Zheng, Y.; Qin, Z.; Wu, B.; Dai, Y.; Gao, H.; Yao, Z.; Gonzalez, F.J.; Yao, X. In Vitro Glucuronidation of Wushanicaritin by Liver Microsomes, Intestine Microsomes and Expressed Human UDP-Glucuronosyltransferase Enzymes. Int. J. Mol. Sci. 2017, 18, 1983.

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