Partial characterization of epididymal 5α reductase in the rat

Monsalve, Alejandra Salcedo; Blaquier, Jörge A.

doi:10.1016/0039-128x(77)90135-0

Cited by 46 publications

(19 citation statements)

References 17 publications

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“…Other 3-keto-4-ene steroids (group E), 16␣-OH-P and 6␤-OH-P, inhibited only the 5␣-reductive metabolism without the product inhibition effects on the oxidative metabolism producing themselves. It is noteworthy that 16␣-OH-P, as well as 20␣-OH-P and 4-AN-CA already reported by other investigators (19,20), were of the 3-keto-4-ene steroids showing the strongest inhibitory effect on the 5␣-reductase activity. Finally, the group F steroids, 11␣-OH-P and cholesterol, showed a slight effect or no effect on both of the metabolisms.…”

Section: Classification Of Various Steroids Based On Their Respectivementioning

confidence: 67%

“…2 As regards another interesting finding obtained from the present study, it has been reported that endogenous COR production in rat adrenal cortex is suppressed by exogenously administrated COR or cortisol in in vivo and in cell culture systems and that this inhibition probably results from the various effects of these steroids, namely inhibiting ACTH secretion from the pituitary, decreasing ACTH sensitivity of adrenal cortex (23), and stimulating the adrenal 5␣-reductase activity metabolizing COR into its 5␣-reduced products (24). However, several recent studies have clearly shown that the two 11␤-OH corticosteroids, COR and cortisol, are of the poorest substrate group for 5␣-reductases of various organs probably including the adrenal cortex itself (19,20,25), and we showed in the present study that COR and 11␤-OH-P, but not 11␣-OH-P, rather stimulated [ 3 H]PROG 5␣-reductase activity of rat liver microsomes (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

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Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes

Yamada¹,

Yamada²,

Fujita³

et al. 2001

Journal of Biological Chemistry

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It is well known that several 3-keto-4-ene steroids such as progesterone and testosterone are metabolized in a gender-specific or -predominant manner by adult rat liver microsomes. In the male, these steroids are primarily metabolized into two oxidized (16␣-hydroxyl and 6␤-hydroxyl) products mainly by the respective, male-specific cytochrome P450 subforms, CYP2C11 and CYP3A2, while they are primarily metabolized into the 5␣-reduced products by female-predominant 5␣-reductase in the female. These sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control. In the present study, we show that unlabeled 16␣-hydroxyprogesterone and 6␤-hydroxyprogesterone inhibited the 5␣-reductive [ 3 H]progesterone metabolism by adult male rat liver microsomes without significantly inhibiting the CYP2C11 and CYP3A2 activities producing themselves, whereas 3␣-hydroxy-5␣-pregnan-20-one and 5␣-pregnane-3,20-dione not only stimulated the 5␣-reductive metabolism producing themselves but also inhibited the male-specific oxidative metabolism. This finding compels us to propose a novel hypothesis that adult male rat liver microsomes may possess a self-augmentation system regulated by the male-specific products on sexually differentiated steroid metabolism, besides regulation by gene expressions of the related enzymes.It is well established that activities of many steroid-metabolizing enzymes in adult rat liver microsomes are sexually differentiated. The male primarily metabolizes various 3-keto-4-ene steroids such as progesterone (PROG), 1 TEST, and 4-AN into the two oxidized products, 16␣-OH (in some cases, 2␣-OH also) and 6␤-OH products, mainly by the respective, malespecific cytochrome P450 subforms (P450s), CYP2C11 and CYP3A2, whereas the female metabolizes them primarily into the 5␣-reduced products by female-predominant 5␣-reductase (1-10). Expressions of these sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control, with the secretory pattern of GH playing a major role. Intermittent and pulsatile (i.e. male pattern) GH secretion induces CYP2C11 gene expression, whereas a more continuous female pattern represses CYP2C11 and CYP3A2 gene expressions and conversely induces 5␣-reductase gene expression (6, 8 -10). Furthermore, sex hormones are thought to affect indirectly these gene expressions by acting on the hypothalamo-pituitary axis that controls the sexually dimorphic pattern of GH secretion (1-3, 6, 7).In the course of our investigation on structural requirements of substrates and/or inhibitors for active sites of CYP2C11 and CYP3A2 in male rat liver microsomes (to be published elsewhere), we unexpectedly found that male-specific products, 16␣-OH-P and 6␤-OH-P, inhibited female-predominant [ 3 H]PROG 5␣-reductase activity without significantly inhibiting the CYP2C11 and CYP3A2 activities producing themselves, while 3␣-OH-5␣-P and 5␣-P, female-predominant products by the 5␣-reductase, not only stimulated this enzyme acti...

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Section: Classification Of Various Steroids Based On Their Respectivementioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes

Yamada¹,

Yamada²,

Fujita³

et al. 2001

Journal of Biological Chemistry

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“…As the V maJ K m ratio of the type I isozyme still contributes substantially to the total potential in vivo 5 a-R E D activity, an anabolic function for this subtype in rat prostate is plausible. In rat epididymis distinct 5 a -RED activities have been detected in the nucleus and microsomes [23][24][25]. Immunocytochemical studies suggest a microsomal localization of the type I isozyme [9].…”

Section: Discussionmentioning

confidence: 99%

Kinetic analysis of rat steroid 5α-reductase activity in prostate and epididymis homogenates at neutral pH: Evidence for type I activity in epididymis

Span

Benraad

Sweep

et al. 1996

The Journal of Steroid Biochemistry and Molecular Biology

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Im m unocytochem ical studies and m R N A m easu rem en ts have show n th at the rat ep id id ym is-like the rat prostate-expresses both rat steroid 5a-reductase isozym es, i.e. type I and IL So far, enzym e activity m easurem ents in rat epididym is hom ogenates, how ever, do not support the presence o f type I 5a-reductase activity. Incubating hom ogenates o f both tissues w ith a wide range o f substrate concentrations, we were able to detect activity o f both isozym es in rat p rostate and ep id id ym is tissues at neutral pH. In rat prostate the am ount o f type I activity, as m easu red by the J/max at pH 7,0, exceeds that of type II 5a-reductase 50-fold. The efficiency ratio, VmaJ K my o f the type I isozym e accounts for 25% of the total in vivo potential activity. A possible anabolic role for the type I iso zy m e in rat prostate was thus surm ised. In rat epidid ym is the Fmax o f type I and type II 5a-reductase at pH 7.0 were sim ilar. C om parison of the efficiency ratio VmaJ K m o f either iso zy m e in the rat epididym is, however, suggested that the type II isozym e would play the m ajor role in the 5a-re duction o f testosterone at physiological concentrations and at n eu tral pH. The specific localization of the isozym es should be considered to allow for correct quantification o f their in vivo contribution to dihydrotestosterone form ation . C opyright © 1996 E lsevier Science Ltd.

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“…Principal cells are the major cell type of this tissue (Trasler et al 1988) and are particularly sensitive to androgen removal (Moore & Bedford 1979a,b). The major circulating androgen testosterone is metabolized by 5a-reductases into the potent androgen 5a-dihydrotestosterone (DHT; Gloyna & Wilson 1969, Monsalve & Blaquier 1977, Robaire et al 1977. Androgens mediate their effects by diffusing through the plasma membrane and binding to intracellular androgen receptors (ARs).…”

Section: Introductionmentioning

confidence: 99%

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

Hamzeh¹,

Robaire²

2011

Journal of Endocrinology

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Androgens are the primary regulators of epididymal structure and functions. In the classical view of androgen action, binding of androgen to the intracellular androgen receptor (AR) produces the receptor-steroid complex that has high affinity for DNA response elements and regulates the transcription of target genes. In this study, we demonstrate that in epididymal cells, 5a-dihydrotestosterone (DHT) can cause an alternative and rapid response that is independent of AR-DNA interactions and is mediated by activation of signaling pathways through the AR. We examined changes in AKT and extracellular signal-regulated protein kinases (ERK1/2) activation at early time points after DHT supplementation in the mouse proximal caput epididymis-1 cell line. DHT had no significant effect on AKT activation at any time point. However, DHT activated the ERK pathway as early as at 1 min, the pathway remained activated at 10 min, but activation was not sustained at later time points. Interestingly, ERK activation was blocked by hydroxyflutamide (HF), indicating that early ERK activation was an AR-mediated response. DHT phosphorylates steroid receptor co-activator (SRC) kinase, and this activation was required for the ERK response. EGFR and IGF1R were downstream of SRC, and these two receptors together contributed to enhance ERK and cAMP response elementbinding protein (CREB) phosphorylation. We postulate that this rapid action of androgen may ultimately act to modulate the transcription of genes regulated by AR in the nucleus. These results support the hypothesis that DHT can activate a pathway involving the sequential activation of MEK, ERK1/2, and CREB through the EGFR/IGF1R in an epididymal cell line.

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Partial characterization of epididymal 5α reductase in the rat

Cited by 46 publications

References 17 publications

Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes

Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes

Kinetic analysis of rat steroid 5α-reductase activity in prostate and epididymis homogenates at neutral pH: Evidence for type I activity in epididymis

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

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