{"title":"肠道微生物白藜芦醇及其代谢产物抑制人和大鼠性腺3β-羟基类固醇脱氢酶：体外实验、构效关系和硅对接分析","authors":"Yingna Zhai, Chunnan Hu, Huitao Li, Yiyan Wang, Shaowei Wang, Xiaoheng Li, Ren-shan Ge, Qiqi Zhu","doi":"10.1155/jfbc/9934626","DOIUrl":null,"url":null,"abstract":"<div>\n <p><b>Introduction:</b> 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.</p>\n <p><b>Methods:</b> 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.</p>\n <p><b>Results:</b> IC<sub>50</sub> 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<sup>+</sup>-/steroid-binding sites of 3β-HSDs.</p>\n <p><b>Conclusion:</b> 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.</p>\n <p><b>Practical Application:</b> 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.</p>\n </div>","PeriodicalId":15802,"journal":{"name":"Journal of Food Biochemistry","volume":"2025 1","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/jfbc/9934626","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"Yingna Zhai, Chunnan Hu, Huitao Li, Yiyan Wang, Shaowei Wang, Xiaoheng Li, Ren-shan Ge, Qiqi Zhu\",\"doi\":\"10.1155/jfbc/9934626\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n <p><b>Introduction:</b> 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.</p>\\n <p><b>Methods:</b> 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.</p>\\n <p><b>Results:</b> IC<sub>50</sub> 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<sup>+</sup>-/steroid-binding sites of 3β-HSDs.</p>\\n <p><b>Conclusion:</b> 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.</p>\\n <p><b>Practical Application:</b> 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.</p>\\n </div>\",\"PeriodicalId\":15802,\"journal\":{\"name\":\"Journal of Food Biochemistry\",\"volume\":\"2025 1\",\"pages\":\"\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-01-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1155/jfbc/9934626\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Food Biochemistry\",\"FirstCategoryId\":\"97\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1155/jfbc/9934626\",\"RegionNum\":2,\"RegionCategory\":\"农林科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Food Biochemistry","FirstCategoryId":"97","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/jfbc/9934626","RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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
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.
期刊介绍：
The Journal of Food Biochemistry publishes fully peer-reviewed original research and review papers on the effects of handling, storage, and processing on the biochemical aspects of food tissues, systems, and bioactive compounds in the diet.
Researchers in food science, food technology, biochemistry, and nutrition, particularly based in academia and industry, will find much of great use and interest in the journal. Coverage includes:
-Biochemistry of postharvest/postmortem and processing problems
-Enzyme chemistry and technology
-Membrane biology and chemistry
-Cell biology
-Biophysics
-Genetic expression
-Pharmacological properties of food ingredients with an emphasis on the content of bioactive ingredients in foods
Examples of topics covered in recently-published papers on two topics of current wide interest, nutraceuticals/functional foods and postharvest/postmortem, include the following:
-Bioactive compounds found in foods, such as chocolate and herbs, as they affect serum cholesterol, diabetes, hypertension, and heart disease
-The mechanism of the ripening process in fruit
-The biogenesis of flavor precursors in meat
-How biochemical changes in farm-raised fish are affecting processing and edible quality
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