Differences in the Glucuronidation of Resveratrol and Pterostilbene: Altered Enzyme Specificity and Potential Gender Differences

Abstract

Summary Resveratrol, a natural polyphenol found in grapes, berries and other plants, has been proposed as an ideal chemopreventative agent due to its plethora of health promoting activities. However, despite its lofty promise as a cancer prevention agent its success in human clinical trials has been limited due to its poor bioavailability. Thus, interest in other natural polyphenols is intensifying including the naturally occurring dimethylated analog of resveratrol, pterostilbene. The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the metabolism of both resveratrol and pterostilbene. The current study sought to elucidate the UGT family members responsible for the metabolism of pterostilbene and to examine gender differences in the glucuronidation of resveratrol and pterostilbene. We demonstrate that UGT1A1 and UGT1A3 are mainly responsible for pterostilbene glucuronidation although UGT1A8, UGT1A9 and UGT1A10 also had detectable activity. Intriguingly, UGT1A1 exhibits the highest activity against both resveratrol and pterostilbene despite altered hydroxyl group specificity. Using pooled human liver microsomes, enzyme kinetics were determined for pterostilbene and resveratrol glucuronides. In all cases females were more efficient than males, indicating potential gender differences in stilbene metabolism. Importantly, the glucuronidation of pterostilbene is much less efficient than that of resveratrol, indicating that pterostilbene will have dramatically decreased metabolism in humans.

Resveratrol glucuronidation in vitro: potential implications of inhibition by probenecid

“…K m values ranged from 0.029 to 0.13 m m , with an overall mean of 0.046 m m . These K m values are consistent with those reported previously …”

Topical treatment with pterostilbene, a natural phytoalexin, effectively protects hairless mice against UVB radiation-induced skin damage and carcinogenesis

“…following topical administration of Pter, Pter-sulfate and Pter-glucuronide (main Pter-derived metabolites generated under in vivo conditions [39]) increased in the skin. Using pooled human liver microsomes, it was shown that glucuronidation of Pter is much less efficient than that of Resv, thus suggesting that Pter may have decreased metabolism in humans [19]. A fact in favor of the higher bioavailability of Pter versus that of Resv.…”

“…Pterostilbene, has a more favorable pharmacokinetic profile [15][16][17]. Pter contains two methoxy groups and one hydroxyl group while Resv has three hydroxyl groups, in consequence Pter is less susceptible to conjugation metabolism and, thus, a longer halflife is expected [18,19]. The dimethoxy structure of Pter enhances its lipophilicity thus increasing membrane permeability and improving its bioavailability [11,16,18,20].…”

Effect of tannic acid, resveratrol and its derivatives, on oxidative damage and apoptosis in human neutrophils

“…Low bioavailability of resveratrol (3,4',5-trihydroxy-trans-stilbene) upon ingestion resulting from extensive intestine and hepatic conversion to sulphates and glucuronides prompted search for natural or synthetic derivatives with improved pharmacokinetic properties (Ndiaye et al, 2011, Lin et al, 2011, Dellinger et al, 2014.…”