Phase I Metabolism of Pterostilbene, a Dietary Resveratrol Derivative: Metabolite Identification, Species Differences, Isozyme Contribution, and Further Bioactivation

• Published in: Journal of agricultural and food chemistry 2023-01, Vol.71 (1), p.331-346
• Main Authors: Li, Ying, Sun, Changcheng, Zhang, Yutian, Chen, Xiang, Huang, Haoyan, Han, Luyao, Xing, Han, Zhao, Di, Chen, Xijing, Zhang, Yongjie
• Format: Article
• Language: English
• Subjects: Bioactive Constituents, Metabolites, and Functions; Glutathione - metabolism; Humans; Isoenzymes; Quinones; Resveratrol; Species Specificity
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.2c05334

Pterostilbene (PTE), a dietary derivative of resveratrol, displayed pleiotropic health-promoting activities. This study aimed to explore the metabolic profiles and species differences of the phase I metabolism of PTE and to investigate subsequent detoxification after PTE bioactivation. PTE was found to be biotransformed to two pharmacologically active metabolites, pinostilbene and 3′-hydroxypterostilbene, in vivo and in vitro with substantial species differences. Human CYP1A2 was proved to be mainly responsible for the demethylation and 3′-hydroxylation of PTE, with its contribution to a demethylation of 94.5% and to a 3′-hydroxylation of 97.9%. An in vitro glutathione trapping experiment revealed the presence of an ortho-quinone intermediate formed by further oxidation of 3′-hydroxypterostilbene. Human glutathione S-transferase isoforms A2, T1, and A1 inactivated the ortho-quinone intermediate by catalyzing glutathione conjugation, implicating a potential protective pathway against PTE bioactivation-derived toxicity. Overall, this study provided a comprehensive view of PTE phase I metabolism and facilitated its further development as a promising nutraceutical.