Involvement of UDP-glucuronosyltransferases in the extensive liver and intestinal first-pass metabolism of flavonoid baicalein.
OBJECTIVE
The present study aims to investigate the involvement of UDP-glucuronosyltranferase (UGT) in the extensive liver and intestinal first-pass glucuronidation of baicalein (B) in both rats and humans and also to study sulfation and P450 mediated hydroxylation of B.


METHODS
B was incubated with liver and intestine microsome, cytosol, S9 fractions from human, rat and various human recombinant UGT isozymes, respectively. The generated metabolites were identified by HPLC/MS/MS and quantified by HPLC/UV.


RESULTS
Three metabolites of B namely baicalein 7-O-glucuronide (BG), the isomer of baicalein 7-O-glucuronide (BG'), and baicalein sulfate were found. BG, the predominant metabolite of B, was extensively generated in liver and jejunum microsomes in both humans and rats. Its formation was mainly catalyzed by UGT 1A9 and also mediated by UGT 1A1, 1A3, 1A8, 1A7 and 2B15 with different kinetic profiles. UGT 1A8 mediated formation of BG' was mainly found in human intestine and rat liver microsomes. Sulfation and P450 mediated hydroxylation of B were much less significant than glucuronidation.


CONCLUSIONS
Extensive liver and intestinal first-pass glucuronidation of B were found in both humans and rats. Under the current experimental conditions, UGT 1A9 and UGT 1A8 demonstrated the fastest formation rate of BG in human liver preparations and BG' in human intestine preparations, respectively.
Zhang
Li
L
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
Lin
Ge
G
Zuo
Zhong
Z
D000465:Algorithms; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D044950:Flavanones / Q000493:pharmacokinetics*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013431:Sulfates / Q000378:metabolism
D000975:Antioxidants; D044950:Flavanones; D007527:Isoenzymes; D011994:Recombinant Proteins; D013431:Sulfates; C006680:baicalein; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase