The (+)- and (−)-gossypols potently inhibit both 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 in human and rat testes

Hu, Guoxin; Zhou, Hongyu; Li, Xingwang; Chen, Bingbing; Xiao, Ye-Chen; Lian, Qingquan; Liang, Guang; Kim, Howard H.; Zhang, Zhiqiang; Hardy, Dianne O.; Ge, Ren‐Shan

doi:10.1016/j.jsbmb.2009.02.004

Cited by 50 publications

(25 citation statements)

References 18 publications

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“…Microsomal preparations of JEG-3 cells were done as described previously [13]. In brief, cells were scraped and homogenized in cold 0.01 mmol/L phosphate buffered saline (pH 7.2), containing 0.25 mmol/L sucrose, and centrifuged at 700 g for 30 min at 4°C to remove the cellular fragments.…”

Section: Methodsmentioning

confidence: 99%

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The Effects of Fungicides on Human 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in Human Placental Cell Line JEG-3

Cao¹,

Wang³

et al. 2017

Pharmacology

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Placenta secretes a large amount of progesterone and estradiol, which are critical for maintaining pregnancy. In human placenta, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) catalyzes pregnenolone to form progesterone, and aromatase (CYP19A1) catalyzes testosterone into estradiol. Fungicides display antifungal activities and are widely used to prevent fungal infections in agricultural plants. These chemicals include azoles, such as tebuconazole (TEB), triadimefon (TRI), and vinclozolin (VCZ) or organotins, such as tributyltin (TBT) and tetrabutyltin (TTBT). Fungicides may disrupt the activities of these 2 enzymes. In the present study, we investigated the effects of these fungicides on steroid production in a human placental cell line JEG-3 and on HSD3B1 and CYP19A1 activities. Of all fungicides tested at 100 µmol/L, only TBT inhibited pregnenolone-mediated progesterone production in JEG-3 cells by over 50%. Except TTBT, all other 4 fungicides inhibited testosterone-mediated estradiol production by over 50%. TBT was a moderate HSD3B1 inhibitor with a half maximal inhibitory concentration (IC₅₀) of 45.60 ± 0.12 µmol/L. When pregnenolone was used to determine the mode of inhibition, TBT was a competitive inhibitor of HSD3B1. The IC₅₀ values of TEB, TRI, VCZ, and TBT for CYP19A1 were 56.84 ± 0.13, 58.73 ± 0.14, 57.42 ± 0.171, and 4.58 ± 0.048 µmol/L, respectively. TEB, TRI, and VCZ were noncompetitive inhibitors of CYP19A1, while TBT was a competitive inhibitor of this enzyme. Therefore, they are endocrine disruptors.

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Section: Methodsmentioning

confidence: 99%

“…HSD3B1 activity in JEG-3 cell homogenate was measured as described previously with a minor modification [13]. In brief, HSD3B1 activity assay tubes contained 0.2 µmol/L pregnenolone and 0.2 mmol/L NAD + in 250 µL 0.5% Tween-20 PBS.…”

Section: Methodsmentioning

confidence: 99%

The Effects of Fungicides on Human 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in Human Placental Cell Line JEG-3

Cao¹,

Wang³

et al. 2017

Pharmacology

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“…3β-HSD activity in testicular microsomes and Leydig cells was measured as described previously [15]. In brief, 3β-HSD activity assay tubes contained 0.2 µmol L -1 pregnenolone and 40 000 dpm pregnenolone, were added to a 0.5% Tween-20 PBS reaction mixture containing 10 µg rat testis microsomes and 0.1-1 µmol L -1 genistein or equol.…”

Section: β -Hsd Assaymentioning

confidence: 99%

“…Activity of the 17β-HSD3 enzyme in testicular microsomes was measured as described previously [15]. Briefly, assay tubes contained 0.1 µmol L −1 androstenedione and 40 000 dpm genistein or equol for 90 min.…”

Section: β -Hsd3 Assaymentioning

confidence: 99%

Effects of genistein and equol on human and rat testicular 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 activities

Zhao²,

Chu³

et al. 2010

Asian J Androl

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The objective of the present study was to investigate the effects of genistein and equol on 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) in human and rat testis microsomes. These enzymes (3β-HSD and 17β-HSD3), along with two others (cytochrome P450 side-chain cleavage enzyme and cytochrome P450 17α-hydroxylase/17-20 lyase), catalyze the reactions that convert the steroid cholesterol into the sex hormone testosterone. Genistein inhibited 3β-HSD activity (0.2 µmol L -1 pregnenolone) with half-maximal inhibition or a half-maximal inhibitory concentration (IC 50 ) of 87 ± 15 (human) and 636 ± 155 nmol L -1 (rat). Genistein's mode of action on 3β-HSD activity was competitive for the substrate pregnenolonrge and noncompetitive for the cofactor NAD + . There was no difference in genistein's potency of 3β-HSD inhibition between intact rat Leydig cells and testis microsomes. In contrast to its potent inhibition of 3β-HSD, genistein had lesser effects on human and rat 17β-HSD3 (0.1 µmol L -1 androstenedione), with an IC 50 ≥ 100 µmol L -1. On the other hand, equol only inhibited human 3β-HSD by 42%, and had no effect on 3β-HSD and 17β-HSD3 in rat tissues. These observations imply that the ability of soy isoflavones to regulate androgen biosynthesis in Leydig cells is due in part to action on Leydig cell 3β-HSD activity. Given the increasing intake of soy-based food products and their potential effect on blood androgen levels, these findings are greatly relevant to public health.

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“…Homogenate preparations of cells were done as described previously [12] . In brief, cells were homogenized in cold 0.01 mmol/l phosphate buffered saline (pH 7.2), which contained 0.25 mmol/l sucrose, and centrifuged at 700 g for 30 min at 4 ° C to remove the cellular fragments and collect cell homogenate.…”

Section: Cell Viability Assaymentioning

confidence: 99%

Effects of Methoxychlor and Its Metabolite Hydroxychlor on Human Placental 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in JEG-3 Cells

Liu¹,

Mao²,

Bai

et al. 2016

Pharmacology

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Progesterone and estradiol produced by the human placenta are critical for maintenance of pregnancy and fetal development. In the human placenta, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) is responsible for the formation of progesterone from pregnenolone and aromatase (CYP19A1) for the production of estradiol from androgen. Insecticide methoxychlor (MXC) and its metabolite hydroxychlor (HPTE) may disrupt the activities of these 2 enzymes. In this study, we investigated the effects of MXC and HPTE on steroid production in human placental JEG-3 cells and on HSD3B1 and CYP19A1 activities. MXC and HPTE inhibited progesterone and estradiol production in JEG-3 cells. MXC and HPTE were potent HSD3B1 inhibitors with the half maximal inhibitory concentration (IC₅₀) values of 2.339 ± 0.096 and 1.918 ± 0.078 μmol/l, respectively. MXC had no inhibition on CYP19A1 at 100 μmol/l, while HPTE was a weak inhibitor with IC₅₀ of 97.16 ± 0.10 μmol/l. When pregnenolone was used to determine the inhibitory mode, MXC and HPTE were found to be competitive inhibitors of HSD3B1. When cofactor NAD⁺ was used, MXC and HPTE were the noncompetitive inhibitors of HSD3B1. When testosterone was used, HPTE was a mixed inhibitor of CYP19A1. In conclusion, MXC and HPTE are potent inhibitors of human HSD3B1, and HPTE is a weak CYP19A1 inhibitor.

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The (+)- and (−)-gossypols potently inhibit both 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 in human and rat testes

Cited by 50 publications

References 18 publications

The Effects of Fungicides on Human 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in Human Placental Cell Line JEG-3

The Effects of Fungicides on Human 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in Human Placental Cell Line JEG-3

Effects of genistein and equol on human and rat testicular 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 activities

Effects of Methoxychlor and Its Metabolite Hydroxychlor on Human Placental 3β-Hydroxysteroid Dehydrogenase 1 and Aromatase in JEG-3 Cells

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