Disease relevance of Srd5a1

• Furthermore, some of these potent P450(17) alpha inhibitors (27-29) are also powerful inhibitors of steroid 5 alpha-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line [1].
• BACKGROUND: Steroid 5 alpha-reductase is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) [2].

High impact information on Srd5a1

• These findings demonstrate cell-type-specific expression of the steroid 5 alpha-reductase isozymes and underscore their distinct and overlapping functions in androgen physiology [3].
• Genes encoding two isozymes of steroid 5 alpha-reductase with different biochemical properties and tissue distributions have recently been isolated [3].
• To determine whether this control is mediated by dihydrotestosterone or testosterone, we investigated the effect of finasteride, a potent inhibitor of steroid 5 alpha-reductase, on the expression of 5 alpha-reductase in the prostate [4].
• Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase [4].
• We have measured the levels and/or activity of IIA1 (P450a), IIA2 (P450m), IIC11 (P450h), IIC12 (P450i), IIIA2 (a P450p isozyme), and steroid 5 alpha-reductase in liver microsomes from male and female dwarf rats, to test the hypothesis that the expression of these sexually dimorphic enzymes is regulated by GH [5].

Chemical compound and disease context of Srd5a1

• Steroid 5 alpha-reductase is an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) in men [6].

Biological context of Srd5a1

• A 2.1-kilobase cDNA was identified and DNA sequence analysis indicated that the human steroid 5 alpha-reductase was a hydrophobic protein of 259 amino acids with a predicted molecular weight of 29,462 [7].
• Transfection of expression vectors containing the human and rat cDNAs into simian COS cells resulted in the synthesis of high levels of steroid 5 alpha-reductase enzyme activity [7].
• LY207320 is an in vitro inhibitor (estimated IC50 = 0.06 microM) of steroid 5 alpha-reductase that catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT) [8].
• Overall, the present study indicates that prepubertal tamoxifen administration does not interfere with the normal sex differentiation of the gender-dependent hepatic cytochromes P450 and steroid 5 alpha-reductase, but this drug modulates peripubertal androgen imprinting of CYP2C11, CYP3A2, and steroid 5 alpha-reductase in adult female rats [9].
• Inhibition of steroid 5 alpha-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450 [10].

Anatomical context of Srd5a1

• The conversion of testosterone into the more potent androgen, dihydrotestosterone, catalyzed by the enzyme steroid 5 alpha-reductase, is required for the differentiation of male external genitalia [11].
• Here, we report the isolation of cDNA clones encoding the rat steroid 5 alpha-reductase using expression cloning in Xenopus oocytes [11].
• Photoaffinity labeling of steroid 5 alpha-reductase of rat liver and prostate microsomes [12].
• Pretranslational control by thyroid hormone of rat liver steroid 5 alpha-reductase and comparison to the thyroid dependence of two growth hormone-regulated CYP2C mRNAs [13].
• Immunocytochemical localization of 4-ene steroid 5 alpha-reductase type 1 along the rat epididymis during postnatal development [14].

Associations of Srd5a1 with chemical compounds

• The microsomal enzyme steroid 5 alpha-reductase is responsible for the conversion of testosterone into the more potent androgen dihydrotestosterone [7].
• The data suggest that the steroid 5 alpha-reductase gene is differentially regulated by testosterone in androgen-responsive versus non-responsive tissues [11].
• In contrast, phosphoramide mustard treatment (100 mg/kg) did modulate microsomal CYP 2C11 and steroid 5 alpha-reductase activities [15].
• These studies establish that ifosphamide is less potent than cyclophosphamide in modulating the pattern of cytochrome P450 and steroid 5 alpha-reductase expression and that phosphoramide mustard is responsible for the modulation of liver enzyme expression by cyclophosphamide, with acrolein potentiating the modulating activity of the mustard [15].
• The sexually differentiated microsomal enzyme steroid 5 alpha-reductase (NADPH: delta 4-3-oxosteroid 5 alpha-oxido-reductase, EC 1.3.99.5) catalyzes the NADPH-dependent conversion of testosterone to 5 alpha-dihydrotestosterone, a more potent androgen [13].

Other interactions of Srd5a1

• Cyclophosphamide modulates rat hepatic cytochrome P450 2C11 and steroid 5 alpha-reductase activity and messenger RNA levels through the combined action of acrolein and phosphoramide mustard [15].
• Tyrphostin AG18 did not affect mRNA species that are not FSH inducible, such as the ribosomal protein L19, or the constitutively expressed low levels of steroid 5 alpha-reductase mRNA [16].
• NADPH-cytochrome P-450 reductase is not a component of the liver microsomal steroid 5-alpha reductase [17].
• The activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase (from S. hydrogenans), steroid-5 alpha-reductase (from rat prostate), and 3 alpha-hydroxysteroid dehydrogenase (from rat liver) were unaffected by pyrazole 3 [18].

Analytical, diagnostic and therapeutic context of Srd5a1

• The amount of steroid 5 alpha-reductase mRNA in liver increased in response to castration, but remained unchanged in the prostate [11].
• Chimeric steroid 5 alpha-reductase cDNAs composed of different combinations of rat and human exon sequences were created by genetic engineering, expressed in human embryonic kidney 293 cells, and assayed for their sensitivity to finasteride [19].
• Developmental changes in 5 alpha-reductase mRNA concentrations were assessed by probing Northern blots with the full-length cDNA for rat steroid 5 alpha-reductase [20].
• In contrast to once daily subcutaneous injections, continuous testosterone release via subcutaneous implant was ineffective in producing the long-term changes in testosterone 2 alpha-hydroxylase and steroid 5 alpha-reductase activities [21].
• In the therapeutic evaluation, only intratumoral implantation of SR-type 5-FU-loaded microspheres significantly decreased the mortality (P = 0.017) [22].

References