Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms.
Resveratrol (trans-resveratrol, trans-3,5,4'-trihydroxystilbene) is a naturally occurring stilbene analogue found in high concentrations in red wine. There is considerable research interest to determine the therapeutic potential of resveratrol, as it has been shown to have tumour inhibitory and antioxidant properties. This study was performed to investigate the glucuronidation of resveratrol and possible drug interactions via glucuronidation. Two glucuronide conjugates, resveratrol 3-O-glucuronide and resveratrol 4'-O-glucuronide, were formed by human liver and intestinal microsomes. UGT1A1 and UGT1A9 were predominantly responsible for the formation of the 3-O-glucuronide (Km = 149 microM) and 4'-O-glucuronide (Km = 365 microM), respectively. The glucuronide conjugates were formed at higher levels (up to 10-fold) by intestinal rather than liver microsomes. Resveratrol was co-incubated with substrates of UGT1A1 (bilirubin and 7-ethyl-10-hydroxycamptothecin (SN-38)) and UGT1A9 (7-hydroxytrifluoromethyl coumarin (7-HFC)). No major changes were noted in bilirubin glucuronidation in the presence of resveratrol. Resveratrol significantly inhibited the glucuronidation of SN-38 (Ki = 6.2 +/- 2.1 microM) and 7-HFC (Ki = 0.6 +/- 0.2 microM). Hence, resveratrol has the potential to inhibit the glucuronidation of concomitantly administered therapeutic drugs or dietary components that are substrates of UGT1A1 and UGT1A9.
Brill
Shirley S
SS
Toxicology and Metabolism, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
Furimsky
Anna M
AM
Ho
Mark N
MN
Furniss
Michael J
MJ
Li
Yi
Y
Green
Adam G
AG
Bradford
Wallace W
WW
Green
Carol E
CE
Kapetanovic
Izet M
IM
Iyer
Lalitha V
LV
D000818:Animals; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007313:Insecta; D007527:Isoenzymes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism*; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
D020719:Glucuronides; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D000077185:Resveratrol; D013267:Stilbenes; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human