LY191704: a selective, nonsteroidal inhibitor of human steroid 5 alpha-reductase type 1.

Abstract

Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation, growth, and maintenance of the mammalian prostate. Production of DHT from testosterone is catalyzed by two distinct membrane-bound steroid 5a-reductase [5a-reductase; 3-oxo-5a-steroid A4-dehydrogenase; 3-oxo-5a-steroid:(acceptor) AW-oxidoreductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign prostatic hyperplasia (BPH), a disease that occurs almost universally in males, is characterized by obstructive and irritative urinary voiding symptoms and has been associated with an overproduction of DHT. Recently, steroidal inhibitors of 5a-reductase type 2 have been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of 5a-reductase type 1, LY191704 {8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo[f]quinolin-3(2H)-one}. This compound was identified based on its capacity to inhibit 5a-reductase activity in a human genital skin fibroblast cell line (Hs68). Surprisingly, LY191704 is inactive when tested in freshly isolated prostate cells obtained from subjects with BPH, whereas previously described 4-azasteroids are active. LY191704 is, however, a potent inhibitor of the 5a-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5a-reductases expressed from transfected cDNAs in simian COS cells indicates that LY191704 is a specific noncompetitive inhibitor of the human 5a-reductase type 1. Taken together, the results suggest that prostate cells have the capacity to express both 5a-reductase isozymes and that LY191704 may be useful in treatment of human endocrine disorders associated with overproduction of DHT by 5a-reductase type 1.Prostatic hyperplasia is an age-related nonmalignant enlargement of the prostate that can result in development of obstructive and irritative urinary voiding symptoms (1, 2). For >100 years, prostatectomy has been used to treat benign prostatic hyperplasia (BPH) and is now the most common surgery performed in men >65 years old (3). Although prostatic surgery has been greatly refined, it still remains a significant cause of morbidity in elderly men (4). Recent attempts have, therefore, sought to develop pharmacological approaches for the treatment of BPH with the principal focus being on the development of agents that affect the underlying mechanisms leading to prostatic hyperplasia.Male sexual tissues show a profound dependence on the continuous presence of androgens for normal growth and function (5-8). Whereas testosterone is produced by the testes, dihydrotestosterone (DHT) is produced from testosterone in tissues by an NADPH-dependent reaction catalyzed by the membrane-bound enzyme Sa-reductase [3-oxo-The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. 5a-steroid A4-dehydrogenase; 3-oxo-5a-steroid:(acceptor) A4-oxidoreductase, EC 1.3.99.5] (9). Testosterone...

The localisation and expression of 5 alpha-reductase types I and II mRNAs in human hyperplastic prostate and in prostate primary cultures

“…It was however interesting to note that our observations on the expression of 5 R-I mRNA in epithelial cells confirm the earlier reports of 5 R-I enzyme in primary culture demonstrating that 5 R activity in primary epithelial cultures from BPH, inferred as the 5 R activity in these cells, was far more susceptible to 5 R-I inhibitors than to 5 R-II inhibitors (Hirsch et al 1993). Whilst it was not possible for us to quantify the relative activity of each isoenzyme in the primary cultures, the combined activities of 5 R-I and -II isoenzymes appeared to be slightly higher in the epithelial cells than in the fibroblast/stromal cultures.…”

“…However the possible presence of 5 R-I in human prostate remains controversial. Whilst some studies reported the absence of 5 R-I mRNA and protein in human prostate (Thigpen et al 1993, Silver et al 1994, other investigations demonstrated 5 R-I expressed in primary prostate tissue by Northern analysis (Bonnet et al 1993) and in cultures of epithelial cells (Hirsch et al 1993). However neither study addressed the important issue of whether the two isoenzymes were expressed in intact BPH tissue or established their cellular distribution within the gland.…”

5α-reductase and 17β-hydroxysteroid dehydrogenase expression in epithelial cells from hyperplastic and malignant human prostate

“…In our earlier studies (Délos et al, 1995), as expected from results on DU145 cells (Kaefer et al, 1996;Délos et al, 1994) (derived from a metastasis of an epithelial human prostate carcinoma) and on benign prostatic hyperplasia (BPH) cells maintained in culture for several days (Hirsch et al, 1993), we have detected 5␣-R1 in cultured prostate epithelial cells. However, we detected no 5␣-R1 in fibroblasts and, paradoxically, no 5␣-R2 in either epithelial cells or fibroblasts passaged twice (Délos et al, 1995) despite the presence of 5␣-R2 in freshly isolated prostate cells (Hirsch et al, 1993). These, however, may have been contaminated with tissue fragments and/or fibroblasts.…”

Depot Medroxyprogesterone in the Management of Benign Prostatic Hyperplasia

“…Their side effects such as impotence, loss of libido and decreased ejaculate volume were not as severe. No hot flashes were reported [2], Androgens, par ticularly dihydrotestosterone, play a major role in differ entiation, growth and maintenance of the human prostate [9,10], Production of dihydrotestosterone from testoster one is catalyzed by two isozymes designated 5a-reductase types 1 and 2 [9], Studies have revealed that type 2 is the predominant isozyme in the genital tissue, including the prostate. Type 1 is expressed in the skin throughout the body [11].…”