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PubMed1990

Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases.

The microsomal enzyme steroid 5 alpha-reductase is responsible for the conversion of testosterone into the more potent androgen dihydrotestosterone. In man, this steroid acts on a variety of androgen-responsive target tissues to mediate such diverse endocrine processes as male sexual differentiation in the fetus and prostatic growth in men. Here we describe the isolation, structure, and expression of a cDNA encoding the human steroid 5 alpha-reductase. A rat cDNA was used as a hybridization probe to screen a human prostate cDNA library. 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. A comparison of the human and rat protein sequences revealed a 60% identity. 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. Both enzymes expressed in COS cells showed similar substrate specificities for naturally occurring steroid hormones. However, synthetic 4-azasteroids demonstrated marked differences in their abilities to inhibit the human and rat steroid 5 alpha-reductases.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Identification and selective inhibition of an isozyme of steroid 5 alpha-reductase in human scalp.

Steroid 5 alpha-reductase (EC 1.3.1.22) catalyzes the reduction of testosterone to dihydrotestosterone. The 5 alpha-reductase found in human scalp has been compared with the enzyme found in prostate. The scalp reductase has a broad pH optimum centered at pH 7.0. This is distinctly different from the pH optimum of 5.5 observed with the prostatic form of the enzyme. These enzymes also differ in the Km for testosterone, which is 25-fold higher for the scalp reductase. The most significant difference between the two enzymes is their affinity for inhibitors. Two 4-azasteroids and a 3-carboxyandrostadiene are potent inhibitors of the prostatic reductase but are weak inhibitors of the scalp reductase. In contrast, several N-4-methylazasteroids are good inhibitors of the scalp reductase. These findings support a proposal that different isozymes of 5 alpha-reductase may exist in scalp and prostate. The scalp reductase was also compared to 5 alpha-reductase 1, one of the two enzymes recently cloned from human prostate [Andersson, S. & Russell, D. W. (1990) Proc. Natl. Acad. Sci. USA 87, 3640-3644; and Andersson, S., Berman, D. M., Jenkins, E. P. & Russell, D. W. (1991) Nature (London) 354, 159-161]. The characteristics of the cloned reductase 1 are comparable to those of the scalp reductase.

Animals↗
PubMed1994

5 alpha-reductase inhibitors and prostatic disease.

5 alpha-Reductase inhibitors are a new class of substances with very specific effects on type I and type II 5 alpha R which may be of use in the treatment of skin disease, such as male pattern baldness, male acne and hirsutism, as well as prostatic hyperplasia and prostate cancer. At least two types of 5 alpha R inhibitors with a different pH optimum have been described. cDNA encoding for both the type I and the type II enzyme has been cloned. Most of the orally effective 5 alpha R inhibitors belong to the class of 4-azasteroids. The radical substituted in the 17 position of the steroid ring seems to be related to species specific variations and to the types of 5 alpha R enzymes in different species and organ systems. 5 alpha R inhibitors lead to a decrease of plasma DHT by about 65% while there is a slight rise in plasma testosterone. The decrease of tissue DHT in the ventral prostate of the intact rat, the dog and in humans is more pronounced and amounts to about 85%. There is a reciprocal rise of tissue T in these systems. The application of an inhibitor of 5 alpha R type II leads to a shrinkage of BPH in men by about 30%. In the rat a similar shrinkage accompanied by a significant decrease of total organ DNA occurs. This decrease, however, is not as pronounced as can be achieved with castration.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions.

The enzyme steroid 5 alpha-reductase (5 alpha-reductase) catalyzes the reduction of delta 4,5 double bonds in a variety of substrates and is thought to play both catabolic and anabolic roles in steroid hormone metabolism. Here, we describe the isolation and characterization of a cDNA encoding the rat type 2 isozyme of 5 alpha-reductase and compare the kinetic properties and tissue-specific expression patterns of this isozyme with those of the type 1 isozyme. The type 2 isozyme has apparent Km values in the nanomolar range for steroid substrates, whereas the type 1 isozyme has micromolar affinities. The isozymes differ in their inhibition by various 4-azasteroids with the type 2 isozyme showing exquisite sensitivity (Ki = 40 pM) to 21,21-pentamethylene-4-aza-5 alpha-pregn-1-ene-3,20-dione. Messenger RNAs encoding the type 2 isozyme are more abundant than type 1 mRNAs in most male reproductive tissues, whereas the type 1 mRNAs predominate in peripheral tissues. Both 5 alpha-reductase mRNAs are more efficiently induced by dihydrotestosterone than by testosterone in the regenerating prostate. The differences in substrate affinities and tissue distributions of the 5 alpha-reductase isozymes suggest that type 2 plays an anabolic role and type 1 a catabolic role in the metabolism of androgens and other steroid hormones.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1980

The effect of the steroid muscle relaxant pipecurium bromide on the acetylcholinesterase activity of red blood cells in vitro.

The acetylcholinesterase (AchE) inhibitory effect of a muscle relaxant 2 beta,16 beta-bis-(4'-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), was studied in vitro. The inhibition of AchE activity of human red blood cells, expressed as pI50, was 3.99, whereas that of serum cholinesterase (ChE) was 4.33. The AchE inhibitor action was reversible. The inhibition was not influenced by the combined administration of promethazine or atropine. The combined effect of pipecurium bromide and of some other diamino-azasteroid agent proved to be additive. Pipecurium bromide showed mixed-type inhibitory effect both on AchE and ChE.

Acetylcholinesterase↗
PubMed1984

Inhibition of S-adenosyl-L-methionine sterol-C-24-methyltransferase by analogues of a carbocationic ion high-energy intermediate. Structure activity relationships for C-25 heteroatoms (N, As, S) substituted triterpenoid derivatives.

Microsomes from maize seedlings are capable of catalyzing the C-24 alkylation of 4,4,14 alpha-trimethyl-9 beta,19-cyclo-5 alpha-cholest-24-en-3 beta-ol (cycloartenol) by (S)-adenosyl-L-methionine (AdoMet) leading to 24-methylene cycloartanol. Derivatives of cycloartenol bearing a nitrogen atom at C-25 have been previously shown to be potent inhibitors of the AdoMet-cycloartenol-C-24-methyltransferase (Narula, A. S., Rahier, A., Benveniste, P., and Schuber, F. (1981) J. Am. Chem. Soc. 103, 2408-2409). In order to determine the molecular parameters of the inhibition and to gain information about its mechanism, various azasteroids and analogues have been synthesized and assayed. The following results have been obtained. i) The presence of a positive charge at position 25 was found to be the major cause of the inhibition since electrostatically neutral isosteric compounds possessing a carbon in place of the nitrogen atom were not inhibitory. The positive charge leading to inhibition may be conferred by a protonated amine, a quaternary ammonium group, as well as by a sulfonium or an arsonium group. ii) A steroid-like structure of the inhibitor was also important. And iii) the presence of a free 3 beta-hydroxy group and the bent conformation of cycloartenol, which are essential molecular features of the substrate for the methylation reaction, were no longer required to observe inhibition. The data obtained strongly support the idea that C-25 heteroatoms (N, As, and S), substituted triterpenoid derivatives possessing a positive charge at position 25, are analogues of a carbocationic high-energy intermediate involved during the reaction catalyzed by the AdoMet-cycloartenol-C-24-methyltransferase.

Indicators and Reagents↗
PubMedDate not supplied

Pharmacodynamic modeling of finasteride, a 5 alpha-reductase inhibitor.

Finasteride is a 4-azasteroid inhibitor of one isoenzyme of 5 alpha-reductases that converts testosterone to dihydrotestosterone (DHT). We characterized the time course of DHT concentrations. The following model was used to assess DHT pharmacodynamics: [formula: see text] where joint fitting of three dose levels yielded kin0 = 28% change/hour, kout = 0.28 hour-1, IC50 = 0.012 ng/ml, and Emax = 0.7. The modification of a previous model with the maximum partial effect factor, Emax, may be useful in characterizing the pharmacodynamics of drugs with similar indirect mechanisms.

Dihydrotestosterone↗
PubMedDate not supplied

In vitro biotransformation of finasteride in rat hepatic microsomes. Isolation and characterization of metabolites.

Metabolism of finasteride ([N-(1,1-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta- carboxamide]; MK-906), a new type of specific inhibitor of testosterone 5 alpha-reductase, was investigated using rat hepatic microsomes. The metabolism of finasteride by rat hepatic microsomes was oxygen- and NADPH-dependent, and addition of metyrapone, 7,8-benzoflavone, and cytochrome c to the incubation mixture inhibited the metabolism of finasteride. It is suggested that the metabolic reaction of finasteride was mediated by a mixed function oxidase involving P-450. Four major metabolites were detected in vitro on incubating finasteride with hepatic microsomes of rats treated with phenobarbital (PB-Ms), whereas two major metabolites were found in the incubation mixture with microsomes of untreated rats (UT-Ms). These metabolites were isolated and purified by solvent extraction and semi-preparative HPLC, and identified by MS spectrometry and NMR spectroscopy. The metabolites consisted of omega-hydroxy finasteride (M-1), finasteride-omega-al (M-2), finasteride-omega-oic acid (M-3), and 6 alpha-OH finasteride (M-4). M-1 and M-4 are the major metabolites in UT-Ms, and M-1 and M-3 in PB-Ms. These studies revealed that hydroxylation of the t-butyl group and ring hydroxylation at the 6-position were key steps in the metabolism of finasteride in the rat hepatic microsomes. Further, the major metabolite M-4 was hydroxylated at the 6 alpha-position, but not at the 6 beta-position of the drug. This finding suggests the existence of a novel enzyme that catalyzes the 6 alpha-hydroxylation of the 4-azasteroid.

Animals↗
PubMedDate not supplied

[The immunobiological properties of trimezon and levamisole on models of humoral and cell-mediated immunogenesis].

It was shown in mice experiments that intragastric administration of the low-molecular synthetic immunomodulator of the 8-azasteroid series trimesone increases the immune response of humoral and cell-mediated types to the thymus-dependent antigen, the sheep erythrocytes. The stimulating effect of the drug in vivo is determined by the dose, the antigen load, and the animals' genotype and does not yield to the effect of levamisole or exceeds it in identical experimental conditions.

Adjuvants, Immunologic↗
PubMed1996

Glycine and GABA receptors: molecular mechanisms controlling chloride ion flux.

We have been able to show that the three clearly identified atoms common to the inhibitory neurotransmitters glycine and GABA, that we previously hypothesized to serve as attachment points at the glycinergic and gabanergic receptor, can indeed interact through both electrostatic and hydrogen bonding to several amino acids, which have been identified in molecular biological investigations as both present and critical in the physiological functioning of key polypeptides common to these inhibitory receptors. In addition, amino acids also involved in stabilizing the interaction between the antagonists strychnine and R5135 at the glycinergic and gabanergic receptors, respectively, have been shown to fit our complex model. We identify in detail molecular mechanisms to explain how glycine and GABA initiate chloride ion movement from extraneuronal fluid in the synaptic cleft to intraneuronal volume. In addition, we also identify the molecular mechanisms involved in the blocking of chloride ion movement by strychnine at the glycinergic receptor and by R5135 at the gabanergic receptor. We also present two computer-generated color prints, one for the glycine receptor and one for the GABA receptor, which show the quantum mechanically geometry optimized complex formed between receptor side chains, i.e., the part of the amino acids in the polypeptide that interacts with the zwitterionic inhibitory neurotransmitters. These computer-generated color figures also show a) the important electrostatic and hydrogen bonding in these interactions, b) a van der Waals model of this complex to illustrate that no steric repulsions exist, and c) the molecular electrostatic potential energy map showing the electrostatic potentials of neurotransmitter bound to the receptor model. Finally, we show with computer calculations that the pseudo-rings, formed between the positive quanidinium group in arginine and one of the oxygen atoms in the carboxyl group in both glycine or GABA, result in a positive planar region which appears to be involved in a charge-transfer complex with aromatic benzene groups in amino acids such as phenylalanine and tryosine.

Androstanes↗
PubMed1992

Determination of L-654,066, a new 5 alpha-reductase inhibitor in plasma by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry.

L-654,066 is a new 5 alpha-reductase inhibitor. A sensitive and specific assay based on combined liquid chromatography/mass spectrometry has been developed for the determination of this drug candidate in plasma. The analyte was isolated from plasma by solid-phase extraction on a C-18 cartridge. A related substance, L-683,838, was used as the internal standard. Extracts were chromatographed on a 5 cm C18 reverse-phase high-performance liquid chromatography column interfaced via the heated nebulizer probe to a corona discharge chemical ionization source. The mass spectrometer was operated in the positive ion tandem mode. The method has sufficient sensitivity, precision, accuracy and selectivity for the analysis of clinical samples containing L-654,066 at concentrations in the range 0.5-20 ng ml-1. The chromatographic run time is less than 2 min.

Azasteroids↗
PubMed1983

Chromosome damage and SCE induced by the cytostatic factor homo-aza-steroidal ester of P-bis (2-chloro-ethyl) amino phenyl acetic acid in CHO cells in culture.

The cytogenetic effects of homo-aza-steroidal ester (ASE) on Chinese hamster ovary (CHO) cells in vitro are reported. It was found that treatment of cells with a dose as low as 0.025 micrograms/ml of ASE causes a significant number of abnormal metaphases containing mostly chromatid-type aberrations. Similarly, significant frequencies of SCE were induced with only 0.075 micrograms/ml of ASE.

Animals↗
PubMedDate not supplied

Inhibition of 5 alpha-reductase activity and alteration of nuclear testosterone. Dihydrotestosterone ratio in human genital skin fibroblasts.

17 beta-N, N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) inhibits 5 alpha-reductase activity in cultured human genital skin fibroblasts. Enzyme kinetic studies analyzed by Eadie-Hofstee plots demonstrated that 4-MA is a competitive inhibitor, with an apparent Ki of 15 nM. 4-MA had a very low binding affinity for the androgen receptor. When fibroblasts were incubated in the presence of testosterone (T) and 4-MA, nuclear uptake of 5 alpha-dihydrotestosterone (DHT) decreased in parallel with the inhibition of 5 alpha-reductase activity. While the overall sum for the nuclear uptake of T and DHT diminished, the nuclear uptake of T increased. Biological androgen inactivity cannot be precluded on the basis of nuclear T plus DHT uptake.

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

Effect of MK-906, a specific 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates in normal men.

To determine the hormonal effects of MK-906, an orally active 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates, 12 healthy men were given 10, 20, 50, and 100 mg MK-906 2 weeks apart in randomized order in a 4-period crossover design. Serum testosterone (T), dihydrotestosterone (DHT), androstanediol glucuronide, and androsterone glucuronide were measured before and 24 hours after each dose. The effect of MK-906 on glucuronyl transferase activity, the enzyme responsible for androstanediol glucuronide and androsterone glucuronide formation, was assessed in vitro using rat prostate tissue. Serum T levels were unchanged after all doses. Serum DHT, androstanediol glucuronide, and androsterone glucuronide were suppressed by 70, 40, and 56%, respectively, after the 10-mg dose, and by 82, 52, and 66% after the 100-mg dose (P less than 0.02 for the comparison between the 10 and 100-mg doses for all three steroids), respectively. Baseline serum T and DHT levels were strongly correlated (R = 0.89, P = 0.0002), as were androstanediol glucuronide and androsterone glucuronide levels (R = 0.78, P = 0.003), but there was no correlation between DHT levels and the levels of either conjugated steroid. MK-906 had no effect on glucuronyl transferase activity in vitro. It was concluded that single doses of MK-906 suppress both conjugated and unconjugated 5 alpha-reduced androgens. While all three steroids appeared to be good markers of systemic 5 alpha-reductase inhibition, further research will be needed to determine which steroid best reflects tissue DHT levels in patients receiving these inhibitors.

5-alpha Reductase Inhibitors↗