Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

Abstract

Resveratrol (3, 5, 4'-trihydroxy-trans-stilbene), a natural polyphenol present in grapes and peanuts, has been reported to exert a variety of potentially therapeutic effects. The aim of this study was to determine the contribution of the gastrointestinal (GI) tract to the glucuronidation of this compound and its cis-isomer, which also occurs naturally. For this purpose, glucuronidation of the two resveratrol isomers was investigated in human microsomes prepared from: stomach, duodenum, four segments of the remaining small intestine (S-1 to S-4) and colon, and from the human intestinal cell lines Caco-2 and PD-7. cis- and trans-Resveratrol were efficiently glucuronidated in the GI tract with the formation of both 3-O- and 4'-O-glucuronides, however, the two stereoisomers were glucuronidated at different rates depending on the donor and the segment considered. Microsomes prepared from Caco-2 and PD-7 cells also efficiently glucuronidated cis-resveratrol and, to a lesser extent, the trans-isomer, however, only the 3-O-glucuronide was formed. Among the UDP-glucuronosyltransferases (UGT) that are known to be expressed in the GI tract, the isoforms UGT1A1, 1A6, 1A8, 1A9 and 1A10 were active in glucuronidating trans- and/or cis-resveratrol. The results demonstrate that the GI tract may contribute significantly to the first pass metabolism of these naturally occurring polyphenols.

Characterizing the Effects of Common UDP Glucuronosyltransferase (UGT) 1A6 and UGT1A1 Polymorphisms oncis-andtrans-Resveratrol Glucuronidation

“…3B depicts the results obtained with UGT1A6-genotyped livers. cis-R3G was formed to a greater extent than cis-R4ЈG, as has been previously reported (Aumont et al, 2001;Sabolovic et al, 2006). The velocities in UGT1A6 *1/*2 and *2/*2 livers were significantly different ( p Ͻ 0.05) from that in UGT1A6 *1/*1 livers for the formation of cis-R3G.…”

“…cis-RES glucuronidation was studied in UGT1A6 recombinant Supersomes and other protein sources to determine and characterize kinetic profile(s) for the formation of the two known metabolitescis-R3G and cis-R4ЈG (Aumont et al, 2001;Sabolovic et al, 2006). Only cis-R3G was formed at the concentration range studied (0 -2000 M).…”

“…UGT1A1 catalyzes the glucuronidation of trans-RES preferentially at the 3 position, yielding the major 3-O-glucuronide (R3G) metabolite, and less so at the 4Ј position to give the minor metabolite [trans-RES 4Ј-O-glucuronide (R4ЈG)]. UGT1A6 selectively glucuronidates the cis-isomer of RES at the 3 position to give the major metabolite [cis-RES 3-O-glucuronide (cis-R3G)], whereas UGT1A9 has been shown to glucuronidate both isomers (Aumont et al, 2001;Sabolovic et al, 2006). The relative contribution of UGT1A9 and UGT1A6 to cis-RES glucuronidation is not clearly established.…”

Resveratrol: A multitargeted agent for age-associated chronic diseases

“…132 In yet another vitro study using Caco-2 cells, resveratrol 3-sulfate and resveratrol 3-glucoronide were the major phase II biotransformation products. 133 These in vitro studies confirm that resveratrol is fairly well absorbed and metabolized in the small intestine.…”

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

“…14,15) Therefore, glucuronidation of drugs in the intestine has been studied using Caco-2 cells. [16][17][18] In contrast, the Caco-2 cell line had not been employed to examine the intestinal metabolism of CYP3A4 substrates due to its lack of CYP3A4 expression. Recently, however, it has been reported that CYP3A4 in Caco-2 cells is induced by 1a,25-dihydroxyvitamin D 3 (VD 3 ).…”