Interplay between metabolism and transport of resveratrol

Abstract

Resveratrol exhibits a variety of biological and pharmacological activities despite its extensive metabolism to sulfates and glucuronides in the intestine and liver. The metabolism of resveratrol is cell specific and strongly correlates with enzyme expression levels. However, a high rate of biotransformation, in concert with the action of the efflux transporters MRP2, MRP3, and ABCG2, reduces intracellular resveratrol concentrations, and may thereby decrease its pharmacological activity. Interestingly, biotransformation is also dependent on disease status. For example, significantly greater sulfation of resveratrol occurs in human breast tumor tissue than in adjacent nonmalignant tissue. The observed differences, however, do not correlate with the expression of sulfotransferases responsible for catalyzing resveratrol sulfation, but rather with significantly higher steroid sulfatase mRNA levels. The in vitro activity of resveratrol sulfates may not necessarily reflect their in vivo function, given the fact that ubiquitously existing human sulfatases can convert the metabolites back to active resveratrol in humans.

Protective effect of ursodeoxycholic acid, resveratrol, andN-acetylcysteine on nonalcoholic fatty liver disease in rats

“…Second, UDCA is an inducer of metabolizing enzymes in the gut and the liver (Hempfling et al, 2003). This is particularly important regarding RSV concerning the fact that RSV is extensively metabolized in the gut and the liver (Maier-Salamon et al, 2013).…”

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

“…Indeed, the modifications just mentioned have been long recognized and studied for representative members of this huge family of natural compounds, including resveratrol, which is of specific interest here. Rapid glucuronidation and sulfation in enterocytes, hepatocytes, and other cells (e.g., [14][15][16][17][18][19][20][21]) and re-export to the intestinal lumen by MDR proteins [15,22,23], or possibly OATPs [24], are thought to limit the potential impact of this celebrated "natural drug" in vivo. This is a pity, given the pleiotropic effects this dietary compound is reported to have in important pathophysiological respects (for recent reviews see, e.g., [25][26][27][28][29][30]).…”

“Target-Site” Drug Metabolism and Transport

“…XMEs as well as drug transporters share common regulatory pathways; for example, pregnane X receptor, constitutive androstane receptor, AhR/ARNT, and Nrf2-Keap mediated regulation of protein expression. Overlapping roles of metabolism and transport impact the overall disposition of RES and its conjugates (Maier-Salamon et al, 2013). It therefore becomes important to integrate metabolism and transport of RES across all eliminating organs to understand the target tissue concentrations of the active compound.…”