Conjugate Position of Glucuronide and Sulfate in Piceatannol Derivatives Affects the Stability and Hydrolytic Resistance of the Conjugate in Biological Matrices

Abstract

Piceatannol, a stilbene compound, undergoes a comprehensive phase II metabolism mediated by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) in humans. Despite their well-documented beneficial effects on health, their detailed pharmacokinetic fate, including the metabolite structure and properties, is poorly understood. Thus, we determined the structure of seven glucuronides and six sulfates transformed from piceatannol and its methylated derivatives in recombinant yeast cells expressing UGTs or SULTs. We evaluated their properties in human and rat plasma samples. The conjugate that was substituted at the 3′- or 4′-catecholic hydroxy moiety exhibited increased stability. The sulfatase-mediated hydrolysis assay results in incomplete digestion or compound degradation of certain sulfates, suggesting a potential risk of underestimation by using indirect quantification methods. These findings emphasize the importance of an authentic standard for accurate pharmacokinetic studies of phase II metabolites that will be useful for understanding the mechanisms underlying the functional contribution of piceatannol in the body.