JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Ming Su,Lei Ye,Yunbing Tang,Shaowei Wang,Zhiyan Hu,Huitao Li,Yiyan Wang,Xiaoheng Li,Yi Liu,Ren-Shan Ge
Resveratrol and its analogs are phytochemicals. Human 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1) synthesizes steroid hormones for normal pregnancy or promoting cancer metastasis. Whether they inhibit 3β-HSD1 remains unclear. In this study, the inhibitory potency, mode of action, structure–activity relationship, and docking parameters of resveratrol and its analogs on 3β-HSD1 and rat homolog 3β-HSD4 were analyzed. The inhibitory potency of these chemicals on human 3β-HSD1 was 4,4′-dihydroxystilbene (IC50, 3.68 μM) > pinostilbene (8.07 μM) > pinosylvin (10.60 μM) > lunularin (26.84 μM) > resveratrol (30.20 μM) > dihydroresveratrol (>100 μM) = oxyresveratrol (>100 μM) > dihydropinosylvin (ineffective at 100 μM). Resveratrol analogs and metabolites are mixed or competitive inhibitors of human 3β-HSD1. Resveratrol and 4,4′-dihydroxystilbene inhibited progesterone secretion by human JAr cells at ≥1 μM. Resveratrol (IC50, 32.09 μM) and pinosylvin (34.71 μM) significantly inhibited rat placental 3β-HSD4 activity. Docking analysis shows that resveratrol analogs and metabolites bind the steroid-binding sites of human 3β-HSD1 and rat 3β-HSD4 and interact with the catalytic residues Ser125/Thr125 and Tyr155. The negative correlation of LogP and IC50 values for human 3β-HSD1 indicates that lipophilicity of chemicals plays a critical role in the inhibitory effect of chemicals. In conclusion, 4,4′-dihydroxystilbene, pinostilbene, and pinosylvin effectively inhibit human 3β-HSD1 depending on their lipophilicity, thereby acting as potential therapeutic agents.
研究领域:
生物化学
·
药理学
·
分子生物学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·Vol. 74
·期 32
·25059-25074
·
IF 6.7
Che Huiyi,Ren Xiya,Wang Shaowei,Wang Lingfei,Gong Chaochao,Shu Yu,Tang Yunbing,Zhang Pu,Ge Ren-Shan,Ying Yingfen
Environmental
exposure to herbicides has raised significant
concerns.
However, whether herbicides affect placental 3β-hydroxysteroid
dehydrogenase/Δ 5 -Δ 4 isomerase (3β-HSD)
remains unclear. This study investigated the inhibitory effects of
14 herbicides, especially dinitroanilines, on human (h3β-HSD1)
and rat (r3β-HSD4), key enzymes in progesterone biosynthesis.
In vitro assays showed isopropalin and oryzalin potently inhibited
h3β-HSD1 (IC 50 39.56 and 52.99 μM) via mixed-type
inhibition. Inplacental JAr cells, oryzalin and profluraline suppressed
progesterone synthesis at 100 μM, while isopropalin had no effect.
Species-dependent inhibition was observed; oryzalin was most potent
against r3β-HSD4 (IC 50 33.52 μM), and cyanazine
also inhibited the rat isoform. Molecular docking indicated their
binding to the NAD + -binding pocket. SAR and pharmacophore
modeling identified molecular volume and flexibility as key for h3β-HSD1
potency. Network toxicology linked herbicide exposure to recurrent
pregnancy loss via steroidogenic genes. These findings provide mechanistic
evidence that specific herbicides disrupt progesterone production
and may contribute to adverse reproductive outcomes.
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高影响因子
TOXICOLOGY LETTERS
·
2023
·
IF 3.5
Yingna Zhai,Shaowei Wang,Bingru Zhang,Yunbing Tang,Hong Wang,Jingjing Li,Zhiyan Hu,Yiyan Wang,Huitao Li,Ren-shan Ge
3β-Hydroxysteroid dehydrogenase/steroid Δ 5,4 -isomerase 1 (3β-HSD1) plays a critical role in the biosynthesis of progesterone from pregnenolone in the human placenta to maintain normal pregnancy. Whether they inhibit placental 3β-HSD1 and mode of inhibition remains unclear. In this study, we screened 21 pesticides and fungicides in five classes to inhibit human 3β-HSD1 and compared them to rat homolog 3β-HSD4. 3β-HSD activity was measured by catalyzing pregnenolone to progesterone in the presence of NAD + . Of the 21 chemicals, azoles (difenoconazole), thiocarbamates (thiram and ferbam) and organochlorine (hexachlorophene) significantly inhibited human 3β-HSD1 with half maximal inhibitory concentration (IC 50 ) values of 2.77, 0.24, 0.68, and 17.96 μM, respectively. We also found that difenoconazole, ferbam and hexachlorophene are mixed/competitive inhibitors of 3β-HSD1 while thiram is a mixed/noncompetitive inhibitor. Docking analysis showed that difenoconazole and hexachlorophene bound steroid-binding site. Difenoconazole and hexachlorophene except thiram and ferbam also significantly inhibited rat 3β-HSD4 activity with IC 50 of 1.12 and 2.28 µM, respectively. Thiram and ferbam significantly inhibited human 3β-HSD1 possibly by interfering with cysteine residues, while they had no effects on rat 3β-HSD4. In conclusion, some pesticides potently inhibit placental 3β-HSD, leading to the reduction of progesterone formation.
研究领域:
药理学
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毒理学
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生殖生物学
·
酶学
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高影响因子
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
·
2023
·
IF 4.1
Zheyuan Ren,Yang Yu,Zhongyao Ji,Huitao Li,Xiaoheng Li,Han Lin,Renshan Ge,Qiqi Zhu
The potential inhibitory effects of flavonoids on gonadal steroid biosynthesis have gained attention due to their widespread presence in natural plant sources. Specifically, our study focused on evaluating the inhibitory efficacy of these compounds on human 3β-hydroxysteroid dehydrogenase 2 (h3β-HSD2) and rat homolog r3β-HSD1, enzymes responsible for the conversion of pregnenolone to progesterone . Through our investigations, we observed that the potency of flavonoids was silymarin (IC 50 , 1.31 μM) > luteolin (4.63 μM) > tectorigenin > (5.86 μM), and rutin (44.12 μM) in inhibiting human KGN cell microsomal h3β-HSD2. Similarly, the potency of flavonoids was silymarin (9.50 μM) > luteolin (11.49 μM) > tectorigenin (14.06 μM), and rutin (145.71 μM) in inhibiting rat testicular r3β-HSD1. Silymarin, luteolin, and tectorigenin acted as mixed inhibitors of both human and rat 3β-HSDs. Luteolin and tectorigenin were able to penetrate human KGN cells to inhibit progesterone secretion . Furthermore, docking analysis and structure-activity relationship analysis highlighted the importance of hydrogen bond formation for the inhibitory efficacy of these compounds against h3β-HSD2 and r3β-HSD1. Overall, this study demonstrates that silymarin exhibits the most potent inhibition of human and rat gonadal 3β-HSDs, and significant SAR differences exist among the tested compounds.
研究领域:
药理学
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生物化学
·
分子生物学
·
内分泌学
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Xin Zhao,Ting Hao,Jianmin Sang,Miaomiao Xia,Linxi Li,Ren-shan Ge,Congde Chen
Dithiocarbamates have been widely used in various industrial applications, such as insecticides (ferbam) or drug (disulfiram). This study explored the inhibitory effects of dithiocarbamates on human and rat gonadal 3β-hydroxysteroid dehydrogenases (3β-HSD) and investigated the structure-activity relationship and mechanistic insights. The inhibitory activity of six dithiocarbamates and thiourea on the conversion of pregnenolone to progesterone was evaluated using human KGN cell and rat testicular microsomes, with subsequent progesterone measurement using HPLC-MS/MS. The study found that among the tested compounds disulfiram, ferbam, and thiram exhibited significant inhibitory activity against human 3β-HSD2 and rat 3β-HSD1, with ferbam demonstrating the highest potency. The mode of action for these compounds was characterized, showing mixed inhibition for human 3β-HSD2 and mixed/noncompetitive inhibition for rat 3β-HSD1. Additionally, it was observed that dithiothreitol dose-dependently reversed the inhibitory effects of dithiocarbamates on both human and rat gonadal 3β-HSD enzymes. The study also delved into the penetration of these dithiocarbamates through the human KGN cell membrane and their impact on progesterone production, highlighting their potency in inhibiting human 3β-HSD2. Furthermore, bivariate correlation analysis revealed a positive correlation of LogP (lipophilicity) with IC 50 values for both enzymes. Docking analysis indicated that dithiocarbamates bind to NAD + and steroid-binding sites, with some interactions with cysteine residues. In conclusion, this study provides valuable insights into the structure-activity relationship and mechanistic aspects of dithiocarbamates as inhibitors of human and rat gonadal 3β-HSDs, suggesting that these compounds likely exert their inhibitory effects through binding to cysteine residues.
研究领域:
药理学
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毒理学
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内分泌学
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生物化学
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高影响因子
MOLECULAR HUMAN REPRODUCTION
·
2014
·Vol. 20
·期 8
·799-809
·
IF 3.483
Wang Yongjie,Tang Chao,Wu Minglan,Pan Yibin,Ruan Hongfeng,Chen Linling,Yao Hongyi,Zhu Haibin,Wu Ximei
We have previously demonstrated that the reduced form of vitamin C (l-ascorbic acid, AA) is able to induce the production of both steroid and peptide hormones in human choriocarcinoma cells. Here, we attempted to investigate the role and underlying mechanism of the oxidized form of vitamin C, dehydroascorbic acid (DHA), in steroidogenesis in primary human cytotrophoblasts and human choriocarcinoma cells. Messenger RNA and protein levels of steroidogenic enzymes including P450 cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and aromatase were examined by quantitative RT–PCR and western blots, respectively. Progesterone (P4) and estradiol (E2) levels were determined by enzyme immunoassays. Knockdown of c-Jun was achieved by lentivirus-mediated shRNA, and signaling pathways implicated in DHA-induced steroidogenesis were examined by western blots and dual-luciferase assays. DHA dose-dependently induced the expression of steroidogenic enzymes including 3β-HSD1, 17β-HSD1 and aromatase at both mRNA and protein levels, and subsequently increased the production of E2 but not P4. These effects were synergized by diethylmaleate, a glutathione-depleting compound, and α-tocopherol, a reducing agent, but robustly attenuated by inhibition of DHA transportation by phloretin or 2-deoxy-d-glucose. DHA time-dependently inhibited JNK and c-Jun phosphorylation, and dose-dependently reduced AP1 reporter activity. JNK signaling pathway-specific inhibitor SP600125 and c-Jun shRNA both significantly increased the expression of steroidogenic enzymes and E2 production regardless of the presence or absence of DHA. These findings suggest that DHA is able to induce steroidogenesis through inhibition of JNK/c-Jun/AP1 signaling, and may therefore play indispensable roles in pregnancy maintenance.
研究领域:
内分泌学
·
细胞生物学
·
分子生物学
·
生殖生物学
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高影响因子
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