Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Finasteride, a 4-aza steroid compound, is an orally active inhibitor of the 5 alpha-reductase enzyme. 5 alpha-Reductase is necessary for the metabolism of testosterone (T) to dihydrotestosterone (DHT) and is found in high levels only in certain tissues such as the prostate. Finasteride has been shown to markedly suppress serum DHT levels in man without lowering testosterone levels. In patients with benign prostate hyperplasia (BPH), finasteride was found to decrease prostate volume by a mean of 28% over a period of 6 months, without causing clinically significant adverse effects. DHT appears to be the primary androgen for prostatic growth. Selective inhibition of 5 alpha-reductase by finasteride may provide a novel approach to BPH therapy by reducing prostate size without affecting T-dependent processes such as fertility, muscle strength, and libido. The clinical development of finasteride for the treatment of benign prostate hyperplasia is reviewed.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:The clinical development of a 5 alpha-reductase inhibitor, finasteride. 170 60

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1991 Jul
PMID:Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate. 171 82

The present study describes the independent expression of the type 1 and 2 isoforms of human 5 alpha-reductase in the baculovirus-directed insect cell expression system and the selectivity of their inhibition. The catalytic properties and kinetic parameters of the recombinant isozymes were consistent with published data. The type 1 isoform displayed a neutral (range 6-8) pH optimum and the type 2 isoform an acidic (5-6) pH optimum. The type 2 isoform had higher affinity for testosterone than did the type 1 isoform (Km = 0.5 and 2.9 microM, respectively). Finasteride and turosteride were selective inhibitors of the type 2 isoform (Ki (type 2) = 7.3 and 21.7 nM compared to Ki (type 1) = 108 and 330 nM, respectively). 4-MA and the lipido-sterol extract of Serenoa repens (LSESr) markedly inhibited both isozymes (Ki (type 1) = 8.4 nM and 7.2 micrograms/ml, respectively; Ki (type 2) = 7.4 nM and 4.9 micrograms/ml, respectively). The three azasteroids were competitive inhibitors vs substrate, whereas LSESr displayed non-competitive inhibition of the type 1 isozyme and uncompetitive inhibition of the type 2 isozyme. These observations suggest that the lipid component of LSESr might be responsible for its inhibitory effect by modulating the membrane environment of 5 alpha-reductase. Partially purified recombinant 5 alpha-reductase type 1 activity was preserved by the presence of lipids indicating that lipids can exert either stimulatory or inhibitory effects on human 5 alpha-reductase.
J Steroid Biochem Mol Biol 1995 Sep
PMID:Human prostatic steroid 5 alpha-reductase isoforms--a comparative study of selective inhibitors. 757 10

Elevated levels of testosterone 5 alpha-reductase (5 alpha-R) and its product, dihydrotestosterone are associated with a number of androgen-dependent skin conditions. A series of 4-azasteroids were tested in vitro as inhibitors of 5 alpha-R in the isolated anagen human hair follicle. Major structural requirements for maximal 5 alpha-R inhibitory activity include a 4-methyl-4-aza moiety and a bulky, lipophilic side chain at C-17. Only one compound, 17 beta-N,N-diethylcarbamyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), was found to be a potent 5 alpha-R inhibitor in all tissues studied: human hair follicles, foreskin (Ki = 3 nM), genital fibroblasts (Ki = 12 nM), and prostate. 17 beta-Hydroxysteroid dehydrogenase activity was not inhibited by 4-MA. With the exception of 4-MA, azasteroid IC50s varied widely in human prostate vs skin, suggesting the possible existence in man of at least two 5 alpha-R isozymes. Finasteride [N(1,1-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide], a delta 1 orally active, specific 5 alpha-R inhibitor exhibiting no affinity for the androgen receptor, was only modestly active in the hair follicle microassay (IC50 = 200 nM). However, it was a potent in vitro inhibitor of human foreskin and prostate 5 alpha-R. Orally administered to rats finasteride inhibited 5 alpha-R in skin. A vasodilator used to treat male pattern baldness (MPB), minoxidil, was found to be a weak inhibitor of human hair follicle 5 alpha-R (IC50 = 1000 nM). 5 alpha-R activity in frontal scalp hair follicles from a MPB subject was four times higher than in occipital follicles. 4-Azasteroids are efficient inhibitors of human skin 5 alpha-R and offer promise for the treatment of acne, hirsutism and MPB.
J Steroid Biochem Mol Biol 1993 Feb
PMID:Azasteroids as inhibitors of testosterone 5 alpha-reductase in mammalian skin. 843 17

Androgens down-regulate the levels of androgen receptors (AR) and AR mRNA in the penis and prostate of castrated rats, and are assumed to cause their decrease during sexual maturation in the penile smooth muscle of intact rats. In order to determine whether these effects occur directly at the target cell level, and to what extent they are due to testosterone (T) or to their metabolites, we have measured AR mRNA in cultures of smooth muscle cells from the adult rat corpora cavernosa treated in vitro with sex steroids. T at high concentrations (100 nM) acted like dihydrotestosterone (DHT) in increasing moderately the levels of AR mRNA in both proliferating and contact-inhibited cells. However, when conversion of T to DHT was blocked by the 5-alpha reductase inhibitor finasteride, the levels of AR mRNA were considerably down-regulated by T (10-500 nM), particularly in the contact-inhibited cells. Finasteride by itself was inactive. These effects in both types of cultures were inhibited by platelet derived growth factor (PDGF) (20 ng/ml), a growth factor that up-regulates AR mRNA levels, and by fadrozole (100 nM), an aromatase inhibitor of the T/estrogen conversion. Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels. With the exception of PDGF none of the treatments affected significantly cell growth, as measured by DNA synthesis and content. Our results indicate that it is possible to modulate in vitro AR mRNA levels in the penile smooth muscle cells, and that under normal conditions DHT and T act as moderate up-regulators. When DHT formation is inhibited, the aromatization pathway of T to estradiol will prevail and induce a pronounced down-regulation of AR mRNA levels. We assume that the in vivo AR down-regulation in the penile smooth muscle by androgens is an indirect effect mediated by a paracrine or endocrine mechanism elicited in another tissue.
J Steroid Biochem Mol Biol 1993 May
PMID:Testosterone down-regulates the levels of androgen receptor mRNA in smooth muscle cells from the rat corpora cavernosa via aromatization to estrogens. 849 43

Finasteride is a potent 5 alpha-reductase inhibitor which has proven useful in the clinical management of benign prostatic hyperplasia. To determine a potential mode of action for finasteride in prostatic cell proliferation, we have studied the incorporation of [3H]-thymidine into the DNA of cultured epithelial and stromal cells from normal and hyperplastic human prostates. The effects of short treatment with 10(-9) M and 10(-6) M finasteride (48 hrs.) on the incorporation of labelled thymidine were studied. A significant effect of finasteride on prostatic cell proliferation was observed at 10(-6) M for both epithelium and stroma from normal prostate: the rate of thymidine incorporation decreased to 80 +/- 3% (p < 0.001) and 55 +/- 10% (p < 0.01), respectively, compared to the control cells. As observed for normal prostates, this rate of thymidine incorporation was less for hyperplastic epithelium (70 +/- 4%, p < 0.001) than that observed for the hyperplastic stroma (74 +/- 4%, p < 0.01). These data clearly demonstrate that the reduction of the prostate volume observed in BPH treatment by finasteride is partly due to an inhibition of cell proliferation. However, the absence of complete inhibition of cell proliferation at 10(-6) M, a concentration known to strongly inhibit the 5 alpha-reductase activity, supports the hypothesis that factors other than DHT are necessary to induce prostatic cell proliferation.
Cell Mol Biol (Noisy-le-grand) 1996 Jun
PMID:Effect of finasteride (Proscar) on the proliferation of cultured epithelial and stromal cells from normal and hyperplastic human prostates. 882 6

The mechanism of inhibition of the rat types 1 and 2 5alpha-reductase by finasteride was investigated using recombinantly expressed enzymes. These studies revealed that finasteride is a potent, reversible inhibitor of the rat type 1 5alpha-reductase with Ki=10.2+/-1.3 nM. Finasteride is a potent inhibitor of the rat type 2; however, in this case the compound binds to the type 2 isozyme-NADPH complex to form a ternary complex with Ki=1.19+/-0.10 nM, which then rearranges to a high affinity complex (E:I) with a pseudo first order rate constant of 1.62+/-0.22 x 10(-3)/s. The second order rate constant is k3/Ki=1.37+/-0.31 x 10(6) M/s. Heat denaturation of the (type 2 enzyme:inhibitor) complex releases dihydrofinasteride and presumably the NADP+-adduct previously identified with the human 5alpha-reductases. The effects of finasteride were also studied in intact COS cells transiently expressing the rat types 1 and 2 5alpha-reductase. Results with whole cell assays confirm differences in mechanism of inhibition of rat types 1 and 2 5alpha-reductase by finasteride.
J Steroid Biochem Mol Biol 1997 Apr
PMID:Inhibition of rat alpha-reductases by finasteride: evidence for isozyme differences in the mechanism of inhibition. 932 10

The rhesus macaque types 1 and 2 5alpha-reductase (5aR1 and 5aR2) were cloned and expressed in COS cells to facilitate comparison of rhesus and human 5aRs. The deduced protein sequences of the rhesus SaRs shared 94% and 96% identity with the human type 1 and 2 isozymes, respectively. Despite a four amino acid insertion at the N-terminal region of rhesus 5aR1, the biochemical properties of rhesus and human homologs are very similar with respect to pH optimum, Km values for testosterone and progesterone, and inhibition by a variety of inhibitors. As expected, the biochemical properties of the human and rhesus 5aR2 are also very similar. The mechanism of inhibition of the rhesus 5aR1 and 5aR2 by finasteride was investigated in more detail. Finasteride displays time dependent inhibition of the rhesus 5aR1 and 5aR2 with second order rate constants of 4 x 10(3) M(-1) s(-1) and 5.2 x 10(5) M(-1)s(-1). Inhibition of rhesus 5aR2 with 3H-finasteride resulted in 3H bound to the enzyme which is not released by dialysis. Heat denaturation of the [rhesus SaR2:inhibitor] complex releases dihydrofinasteride, a breakdown product presumably related to the NADP+-adduct previously identified with the human SaRs (Bull et al., Mechanism-based inhibition of human steroid 5alpha-reductase by finasteride: Enzyme catalyzed formation of NADP-dihydrofinasteride, a potent bisubstrate analog inhibitor. J. Amer. Chem. Soc., 1996, 118, 2359-2365). Taken together, these results provide good evidence that the rhesus macaque is a suitable model to evaluate the pharmacological properties of finasteride and other 5aR inhibitors.
J Steroid Biochem Mol Biol 1998 Sep
PMID:Cloning, expression and characterization of rhesus macaque types 1 and 2 5alpha-reductase: evidence for mechanism-based inhibition by finasteride. 974 33

Finasteride is a well known steroid 5alpha-reductase inhibitor. In this context, recently we have shown that in human benign prostatic hyperplasia (BPH) finasteride inhibits the 5alpha-reduction of testosterone to dihydrostestosterone (DHT) more effectively in the epithelium as compared to the stroma. The aim of the present study was to describe in epithelium and stroma of human BPH the effect of finasteride on the 5alpha-reduction of androstenedione, that is the second main circulating androgen in men, to androstanedione. Using a finasteride concentration of 75 nM and an androstenedione concentration of 220 nM, the mean inhibition [% +/- SEM] of 5alpha-reductase activity was significantly higher in epithelium (69 +/- 2) than in stroma (52 +/- 4). Both in epithelium and stroma, this inhibition of 5alpha-reductase activity was dose-dependent and competitive. Dixon plots as well as slope replots of Lineweaver-Burk plots showed that the mean inhibition constant Ki (nM +/- SEM) was significantly lower in epithelium (10 +/- 1 and 11 +/- 2, respectively) than in stroma (33 +/- 7 and 28 +/- 4, respectively) indicating a significantly stronger inhibitory effect of finasteride in epithelium. From those mean Ki values, it follows that in human BPH finasteride inhibits equally well both the 5alpha-reduction of androstenedione to androstanedione and testosterone to DHT. Based on these inhibition studies, there is no evidence for the coexistence of substrate-specific 5alpha-reductases converting either testosterone or androstenedione. However, the striking difference in finasteride sensitivity of the 5alpha-reduction between epithelium and stroma could be due to a cell-type specific expression of structurally different 5alpha-reductases as well as to a different access of finasteride to 5alpha-reductase in epithelium and stroma where, compared to each other, the lipid environment is significantly different.
J Steroid Biochem Mol Biol 1998 Oct
PMID:In vitro inhibition of androstenedione 5alpha-reduction by finasteride in epithelium and stroma of human benign prostatic hyperplasia. 978 29

Site directed mutagenesis of human steroid 5alpha-reductase types 1 (5AR1) and 2 (5AR2) has been used to identify residues involved in inhibitor/substrate binding by 5AR2. Replacing residues 21-24 (GALA) in 5AR2 with the analogous residues 26-29 (AVFA) from 5AR1 did not significantly alter either the Km for testosterone or the Ki for the competitive inhibitor Finasteride. Replacement of AVFA in 5AR1 with GALA from 5AR2 however, significantly decreased the Km and increased the resistance to Finasteride. These findings confirm that 5AR1 residues 26-29 are involved in inhibitor/substrate binding but suggest residues 21-24 of 5AR2 are not. Replacing residues 20-29 (QCAVGCAVFA) of 5AR1 with the analogous residues 15-24 (ATLVALGALA) from 5AR2, changed the Km and Ki to values approaching those for wild type 5AR2. Replacing residues VAL in wild type 5AR2 with VGC from 5AR1 did not change Km or Ki but replacing ATL in 5AR2 with QCA from 5AR1 significantly decreased the Km and increased the resistance to Finasteride. Conversely, replacing QCA with ATL in 5AR1 containing GALA in place of AVFA, increased the Km and decreased resistance to Finasteride. These findings indicate residues 15-17 of human 5AR2 participate in inhibitor/substrate binding whereas residues 18-20 do not.
J Steroid Biochem Mol Biol 2001 May
PMID:Structure-function studies of human 5-alpha reductase type 2 using site directed mutagenesis. 1137 83


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