Resveratrol and Its Metabolites by Gut Microbiota Inhibit Human and Rat Gonadal 3β-Hydroxysteroid Dehydrogenases: In Vitro Assay, Structure–Activity Relationship, and In Silico Docking Analysis

Abstract

Introduction: Resveratrol and its analogs have potential therapeutic usage. Resveratrol is metabolized to various metabolites by gut microbiota, including dihydroresveratrol, lunularin, pinostilbene, and oxyresveratrol. However, they might have side effects by inhibiting human gonadal 3β-hydroxysteroid dehydrogenase 2 (h3β-HSD2) and rat homolog r3β-HSD1, thereby interfering with steroid biosynthesis.

Methods: Herein, we analyzed the inhibitory strength via in vitro assay, mode of action, structure–activity relationship, and docking simulation of resveratrol analogs on 3β-HSDs. Human KGN cell microsome was used as h3β-HSD2 source, and 90-day-old male Sprague–Dawley rat testicular microsome was used as r3β-HSD1 source. The conversion of pregnenolone to progesterone by 3β-HSDs was analyzed.

Results: IC₅₀ values for h3β-HSD2 were 4,4′-dihydroxystilbene (8.87 μM) > pinostilbene (10.51 μM) > resveratrol (50.04 μM) > lunularin (96.10 μM), while those for r3β-HSD1 were pinostilbene (5.11 μM) > 4,4′-dihydroxystilbene (15.16 μM) > resveratrol (26.58 μM) > lunularin (34.32 μM). Most resveratrol analogs were mixed/competitive inhibitors of both 3β-HSDs. Lipophilicity (LogP) and lowest binding energy determined the inhibitory strength. Docking analysis showed that resveratrol and its analogs bind to the NAD⁺-/steroid-binding sites of 3β-HSDs.

Conclusion: Resveratrol can inhibit both human and rat gonadal 3β-HSDs, thereby interfering with the metabolism and concentrations of steroid hormones such as progesterone, testosterone, and estradiol.

Practical Application: Consequently, this interference could hold significance for conditions related to hormone imbalances, such as polycystic ovary syndrome and certain cancers. Disorders marked by elevated levels of androgens, like hyperandrogenism, might find therapeutic benefit from interventions aimed at modulating 3β-HSD activity. Hence, resveratrol and its metabolites could present themselves as natural or supplementary treatment options for managing such conditions.