Steroid 5 a-reductase

Steroid 5 a reductase deficiency in man An inherited form of male pseudohermaphroditism. Science 1974 186 1213-5. 

SR039 lehle, C., S. Delos, O. Guirou, R. Tate, ]. P. Raynaud, and P. M. Martin. Human prostatic steroid 5 alpha-reductase isoforms—a comparative study of selective inhibitors. J Steroid Biochem Mol Biol 1995 54(5-6) 273-279. 

The scheme used to produce a somewhat more complex 5-a-reductase inhibitor relies on a chiral auxiliary to yield the final product as a single enantiomer. The first step in a sequence similar to that above starts with the reaction of bromotetralone (23-1) with R-a-phenethyl amine (23-2) to afford the enamine (23-3). Reaction with methyl iodide adds the methyl group at what will be a steroid-like AB ring junction... 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

Propecia Finasteride 1 mg Tablet Male pattern hair loss A specific inhibitor of steroid type II 5 a-reductase Lactose monohydrate, MCC, pregelatinized starch, sodium starch glycolate, docusate sodium, magnesium stearate, Hypromellose 2910 Merck Co. 

Turosteride Pharmacia Non-steroidal teteracyclic structure closely resembles 4-azeisteroid 5 a-Reductase inhibitor BPH, alopecia, acne, hirsutism... 

SAW PALMETTO is the fruit of Sabal serrulata (Mich.) Benth et Hook. (syn. Sermon repms (Bart.) Small), family Arecaceae. The fruits contain fatty acids and steroids, particularly 6-sitosterol, and liquid COj hexane extracts of the berries are commercially available. Pharmacological studies have shown inhibition of 5-a-reductase and a reduction in hormone receptors in prostate tissue. Over 18 clinical trials involving nearly... 

Two recently developed classes of drug show promise, and these act by inhibiting the production of testosterone from cholesterol or its metabolism by the enzyme 5-cc-reductase. Attempts to control benign prostatic hyperplasia provided the incentive for the development of 5-a-reductase inhibitors. It has been known for some time that there is a genetic condition that is manifested by a deficiency of this enzyme. Men who have this gene defect have normal external genitalia but only a very small prostate and additionally, they do not develop acne or exhibit the typical male pattern of hair loss. All of these processes are under the control of 5- -reductase, which controls the conversion of testosterone to another steroid, dihydrotestosterone, and it is an imbalance in the ratio of these two steroids that leads to acne, male-pattern baldness, prostatic hyperplasia and probably prostatic cancer. Several... 

Another plant protein is highly homologous to mammalian steroid 5 ot reductases (see here), which are involved in androgen synthesis. Plants lacking this protein have a growth defect, which can be reversed by brassinolide. Thus, the reductase-like protein is likely involved in the synthesis of a compound very similar (or identical) to brassinolide. 

Ram, P.A. and D.J. Waxman (1990). 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. J. Biol. Chem. 265, 19223-19229. 

We saw in Chapter 3 that bisubstrate reactions can conform to a number of different reaction mechanisms. We saw further that the apparent value of a substrate Km (KT) can vary with the degree of saturation of the other substrate of the reaction, in different ways depending on the mechanistic details. Hence the determination of balanced conditions for screening of an enzyme that catalyzes a bisubstrate reaction will require a prior knowledge of reaction mechanism. This places a necessary, but often overlooked, burden on the scientist to determine the reaction mechanism of the enzyme before finalizing assay conditions for HTS purposes. The importance of this mechanistic information cannot be overstated. We have already seen, in the examples of methotrexate inhibition of dihydrofolate, mycophenolic acid inhibiton of IMP dehydrogenase, and epristeride inhibition of steroid 5a-reductase (Chapter 3), how the [5]/A p ratio can influence one s ability to identify uncompetitive inhibitors of bisubstrate reactions. We have also seen that our ability to discover uncompetitive inhibitors of such reactions must be balanced with our ability to discover competitive inhibitors as well. 

The answer is b. (Idardman, p 1453. Katzung, p 705.) Finasteride is a competitive inhibitor of the steroid 5-reductase, causing reduction in plasma and prostate dihydrotestosterone. Males with benign prostatic hypertrophy (BPH) that are treated with finasteride are found to have decreased prostate size. A change in symptoms related to urination occurs in about one-third of patients... 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Pharmacology Finasteride is a competitive and specific inhibitor of steroid 5 -reductase, an intracellular enzyme that converts testosterone into the potent androgen 5 -dihydrotestosterone (DHT). 

Rationally, 5/3-reduclase deficiency would not be a cause of MPH, but it seems appropriate to place this disorder adjacent to its 5a-counterpart. 5/3-Reductase (AKR1D1) is an essential bile-acid biosynthetic enzyme and patients with disabling mutations in this enzyme have a clinical phenotype associated with cholestasis and fiver failure. In addition to its importance in bile-acid synthesis, this aldoketo-reductase is responsible for reducing approximately two-thirds of the mass of synthesized androgens, corticosteroids, and aldosterone prior to their excretion, so has a vital role in steroid metabolism. 

In the laboratory of D.A. Holt, the synthesis of a new class of steroid 5 -reductase inhibitors was undertaken. They found that unlike the steroidal acrylates, steroidal A ring aryl carboxylic acids exhibit greatly reduced affinity for rat liver steroid 5 -reductase. The tested steroidal A ring carboxylic acids were synthesized from estrone in one example, fluorine was incorporated into the 4-position of estrone via the Balz-Schiemann reaction. 

Specific defects in bile acid synthesis Cerebrotendinous xanthomatosis Intrahepatic cholestasis familial neonatal hepatitis) 3-p-hydroxysteroid dehydrogenase/isomerase deficiency A -3-oxosteroid 5-P-reductase deficiency C24 steroid 7-a-hydroxylase deficiency Peroxisomal disorders... 

Only 2% of total plasma testosterone is present in the physiologically active unbound state. The remaining testosterone is reversibly bound to a steroid hormone-binding globulin. The unbound testosterone or androgen precursors penetrate the prostatic cell by passive diffusion and are converted to DHT by 5-o -reductase. DHT subsequently binds with a specific cytoplasmic receptor. This DHT-receptor complex is then transported to the nucleus of the cell, where transcription and ultimately translation of stored genetic material occur. 

In the presence of 100000 X g supernatant fraction of liver homogenate, 7 -hy-droxy-4-cholesten-3-one as well as 7a,12a-dihydroxy-4-cholesten-3-one are efficiently converted into the corresponding 3a-hydroxy-5 8-steroids via the 3-oxo-5/8-steriods [27,28] (cf. Fig. 3). The NADPH-dependent A -3-oxosteroid 5/S-reductase active on 7a-hydroxy-4-cholesten-3-one and 7a,12 -dihydroxy-4-cholesten-3-one has been partially purified by Bersdus [112,113]. The preparation was also active towards 3-oxo-A -steroids of the C19, Cj, and C24 series. The results of some inhibition experiments indicated that there were different A -3-oxosteroid 5j8-reductases with different substrate specificities in the preparation. 

The incorporation of malonate into mevalonic acid and steroids has been investigated further. Experiments with normal and tumorous rats have demonstrated the previously unsuspected fact that the S-methyl group of methionine is incorporated into cholesterol and cholest-7-en-3jS-ol. Some of the enzymes involved in mevalonate synthesis have been isolated. Yeast acetoacetyl coenzyme A thiolase (EC 2.3.1.9) has a molecular weight of about 190 000 and 3-hydroxy-3-methyl glutaryl coenzyme A synthetase (EC 4.1.3.5) a molecular weight of 130 000. Rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34) used only [4/ - H]NADPH in the formation of mevalonic acid with incorporation of two tritium atoms (at Hp and Hp) (see Scheme 1). 

The enzymes involved in reducing the 4,5 double bond of the A ring of the steroid hormone are called zl " -reductases. These reductases have been found in liver, but they have not been solubilized or purified. The reductases are substrate specific and require NAD as a coenzyme. The specificity of the enzymes also extends to the product, and one can distinguish between zl", 5a-reductases and d, 5j8-reductases. Both types of reductases have been found in liver. Whereas the a-reductase is associated with the microsomal fraction, the jS-reductase is found in liver supernatant. 

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