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

Abstract

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.

Resveratrol Derivatives Inhibit Transthyretin Fibrillization: Structural Insights into the Interactions between Resveratrol Derivatives and Transthyretin

“…Previous research has demonstrated that compound 8 possesses better pharmacokinetic properties, and our current study revealed that it exhibited inhibitory effects on V30M-TTR fibrillization comparable to 1 . Our results also indicated that pinostilbene ( 7 ), a pharmacologically active metabolite of 8 , possessed potent inhibitory potency against V30M-TTR fibrillization . These results suggest that further research is warranted toward the practical applications of 8 .…”

“…36 Our results also indicated that pinostilbene (7), a pharmacologically active metabolite of 8, possessed potent inhibitory potency against V30M-TTR fibrillization. 37 These results suggest that further research is warranted toward the practical applications of 8.…”

Pterostilbene in the treatment of inflammatory and oncological diseases

“…PTS undergoes significant first-pass metabolism in the liver, which is vital for its systemic clearance. This metabolism primarily involves phase II detoxification reactions, predominantly glucuronidation, and sulfation, transforming PTS into more water-soluble forms suitable for excretion ( Kapetanovic et al, 2011 ; Gómez-Zorita et al, 2021 ; Li et al, 2023 ). Compared to RSV, PTS has a much lower glucuronidation efficiency in the liver, affecting its human metabolism ( Dellinger et al, 2014 ).…”

The Research Progress of Extraction, Purification and Analysis Methods of Phenolic Compounds from Blueberry: A Comprehensive Review

“…It also has analgesic, antiaging, antidiabetic, anti-inflammatory, antiobesity, antioxidant, cholesterol-lowering, and neuroprotective properties [25]. Moreover, it depicts higher biological activity, stability, and bioavailability [26]. Pan, J. et al found that pterostilbene is the bioactive component of the blueberry, which reduced serum uric acid and protected the kidneys in hyperuricemic nephropathy (HN) mice by reducing the serum creatinine, urea, urinary albumin, and urinary albumin to creatinine ratio (u-ACR) [27].…”