Use of isoform-specific UGT metabolism to determine and describe rates and profiles of glucuronidation of wogonin and oroxylin A by human liver and intestinal microsomes.
OBJECTIVE
Glucuronidation via UDP-glucuronosyltransferases (or UGTs) is a major metabolic pathway. The purposes of this study are to determine the UGT-isoform-specific metabolic fingerprint (or GSMF) of wogonin and oroxylin A, and to use isoform-specific metabolism rates and kinetics to determine and describe their glucuronidation behaviors in tissue microsomes.


METHODS
In vitro glucuronidation rates and profiles were measured using expressed UGTs and human intestinal and liver microsomes.


RESULTS
GSMF experiments indicated that both flavonoids were metabolized mainly by UGT1As, with major contributions from UGT1A3 and UGT1A7-1A10. Isoform-specific metabolism showed that kinetic profiles obtained using expressed UGT1A3 and UGT1A7-1A10 could fit to known kinetic models. Glucuronidation of both flavonoids in human intestinal and liver microsomes followed simple Michaelis-Menten kinetics. A comparison of the kinetic parameters and profiles suggests that UGT1A9 is likely the main isoform responsible for liver metabolism. In contrast, a combination of UGT1As with a major contribution from UGT1A10 contributed to their intestinal metabolism. Correlation studies clearly showed that UGT isoform-specific metabolism could describe their metabolism rates and profiles in human liver and intestinal microsomes.


CONCLUSIONS
GSMF and isoform-specific metabolism profiles can determine and describe glucuronidation rates and profiles in human tissue microsomes.
Zhou
Qiong
Q
Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, China.
Zheng
Zhijie
Z
Xia
Bijun
B
Tang
Lan
L
Lv
Chang
C
Liu
Wei
W
Liu
Zhongqiu
Z
Hu
Ming
M
D044950:Flavanones / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D020719:Glucuronides / Q000737:chemistry*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms; D000099237:UDP-Galactose Translocators
D044950:Flavanones; D005419:Flavonoids; D020719:Glucuronides; D014453:Glucuronosyltransferase; D009004:Monosaccharide Transport Proteins; D020033:Protein Isoforms; D000099237:UDP-Galactose Translocators; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; C085514:wogonin
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