Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms

Abstract

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.

Pulmonary Metabolism of Resveratrol: In Vitro and In Vivo Evidence

“…Other studies have shown low or no UGT expression in normal human lung tissue (Zheng et al, 2002;Somers et al, 2007;Nakamura et al, 2008). In the present study, the absence of R3G formation in human lung fraction is consistent with low or absent expression of UGT isoforms in normal human lung tissue (Nakamura et al, 2008) responsible for RES glucuronidation (Brill et al, 2006).…”

“…First-pass metabolism by gut, liver, and lungs in series can synergistically increase total body clearance of RES. Although the role of gut and liver in the metabolism of RES is known (Miksits et al, 2005;Brill et al, 2006;Iwuchukwu and Nagar, 2008), the contribution of lungs to RES metabolism has not been evaluated. In the present study, the contribution of lungs in the metabolism of RES was evaluated using multiple sites of administration and a single site of sampling design (Cassidy and Houston, 1980) in a mouse model.…”

“…The species difference in RES glucuronidation at its 3-OH position can be explained by differential expression of urindine 59-diphosphoglucuronosyltransferase (UGT) isoforms in mouse and human lungs. RES has been reported to be glucuronidated at its 3-OH position via UGT1A1, UGT1A7, and UGT1A9, with minor contribution from UGT1A6, UGT1A8, UGT1A10, and UGT2B7 (Brill et al, 2006). Ugt1a6 has been shown to be expressed well in mouse lung (Buckley and Klaassen, 2007) and might be responsible for RES glucuronidation in mouse lungs.…”

“…It also has lung cancer chemopreventive activity by altering the expression of genes involved in the phase 1 metabolism of polycyclic hydrocarbons (Mollerup et al, 2001). Although the role of the gut and liver is well known in the metabolism of RES (Kuhnle et al, 2000;Miksits et al, 2005;Brill et al, 2006;Iwuchukwu and Nagar, 2008;van de Wetering et al, 2009), the role of lungs has not been evaluated in the metabolism of RES. RES is known to be extensively metabolized into its two major metabolites [i.e., trans-resveratrol-3-sulfate (R3S) and trans-resveratrol-3-glucuronide (R3G)] (Fig.…”

Effects of Herbal Supplements on Drug Glucuronidation. Review of Clinical, Animal, andIn VitroStudies

“…However, based on flavonoid content in grape seeds of 4 to 5 %, in vivo quercetin and kaempferol concentrations are not likely to reach inhibitory levels [79]. Resveratrol is also a substrate for UGT1A1 and UGT1A9 enzymes, but no information is available on its potential to modulate UGT enzymes [54,55]. In rats, catechin glucuronides were the primary existing form of catechins in plasma following oral grape seed extract administration [80].…”