Selective non-steroidal inhibitors of 5α-reductase type 1

Occhiato, Ernesto G.; Guarna, Antonio; Danza, Giovanna; Serio, Mario

doi:10.1016/j.jsbmb.2003.10.004

Cited by 54 publications

(36 citation statements)

References 85 publications

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“…Chondrocytes from male and female rats both possess the ability to aromatize testosterone to estrogen, but female cells do so to a greater extent [Sylvia et al, 2002], thereby reducing the testosterone concentration while increasing local levels of estradiol. Testosterone is also metabolized to dihydrotestosterone (DHT) and 5-alphaandrostenedione in epiphyseal cartilage [Jaffe, 1969;Ackerman and Hamilton, 1976;Audi et al, 1984;Takahashi et al, 1984;Blanchard et al, 1991], and in many testosterone-sensitive tissues, DHT is the active metabolite of the hormone [Mauvais-Jarvis, 1986;Horton, 1992;Occhiato et al, 2004].…”

mentioning

confidence: 99%

Sexual dimorphism of growth plate prehypertrophic and hypertrophic chondrocytes in response to testosterone requires metabolism to dihydrotestosterone (DHT) by steroid 5‐alpha reductase type 1

Raz¹,

Nasatzky²,

Boyan³

et al. 2005

J of Cellular Biochemistry

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Rat costochondral growth plate chondrocytes exhibit sex-specific and cell maturation dependent responses to testosterone. Only male cells respond to testosterone, although testosterone receptors are present in both male and female cells, suggesting other mechanisms are involved. We examined the hypothesis that the sex-specific response of rat costochondral cartilage cells to testosterone requires further metabolism of the hormone to dihydrotestosterone (DHT). Resting zone (RC) and growth zone (GC, prehypertrophic and upper hypertrophic zones) chondrocytes from male and female Sabra strain rats exhibited sex-specific responses to testosterone and DHT: only male cells were responsive. Testosterone and DHT treatment for 24 h caused a comparable dose-dependent increase in [3H]-thymidine incorporation in quiescent preconfluent cultures of male GC cells, and a comparable increase in alkaline phosphatase specific activity in confluent cultures. RC cells responded in a differential manner to testosterone and DHT. Testosterone decreased DNA synthesis in male RC cells but DHT had no effect and alkaline phosphatase specific activity of male RC cells was unaffected by either hormone. Inhibition of steroid 5alpha-reductase activity with finasteride (1, 5, or 10 microg/ml), reduced the response of male GC cells to testosterone in a dose-dependent manner, indicating that metabolism to DHT was required. RT-PCR showed that both male and female cells expressed mRNAs for steroid 5alpha-reductase type 1 but lacked mRNAs for the type 2 form of the enzyme. Male cells also exhibited 5alpha-reductase activity but activity of this enzyme was undetectable in female cells. These observations show that sex-specific responses of rat growth zone chondrocytes to testosterone requires the further metabolism of the hormone to DHT and that the effect of DHT in the male growth plate is maturation-state dependent. Failure of female chondrocytes to respond to testosterone may reflect differences in testosterone metabolism, since these cells possess greater ability to aromatize the hormone to estradiol.

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confidence: 99%

Sexual dimorphism of growth plate prehypertrophic and hypertrophic chondrocytes in response to testosterone requires metabolism to dihydrotestosterone (DHT) by steroid 5‐alpha reductase type 1

Raz¹,

Nasatzky²,

Boyan³

et al. 2005

J of Cellular Biochemistry

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“…The identification of two isozymes of 5α-reductase, their relative role in physiological and pathological developments of prostatic diseases has opened the door to synthesize more specific and selective inhibitors. Hundreds of steroidal and non-steroidal inhibitors ranging from classical, reversible and irreversible inhibitors, and transition state analogues to mechanism-based analogues have been synthesized during last two decades [27,28]. These agents suppress the DHT concentration by blocking the enzyme, resulting in shrinkage in the size of prostate, increased peak urinary flow rates and ultimately providing relief [29].…”

Section: α-Reductase Inhibitorsmentioning

confidence: 99%

5α- Reductase Inhibitors in Prostate Cancer: An Overview

Passi¹

2017

Austin J Cancer Clin Res

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Prostate cancer is the noncutaneous malignancy of the prostate gland in elderly men. Steroid 5α-reductase (5AR) enzyme dictates the cellular availability of dihydrotestosterone to prostatic epithelial cells and consequently modulates its growth. Excessive production of DHT has been implicated in the pathogenesis of Prostate cancer. Finasteride and Dutasteride, clinically available 5AR inhibitors may play an important role in the prevention and treatment of prostate cancer by blocking peripheral conversion of T into DHT. This article gives a brief account of biology of prostate, rationale and efficacy of 5AR inhibitors in prostate cancer management and their associated controversies.

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“…The first steroidal RIs were designed by modifications of the T, the natural substrate of the enzyme. One of the main modifications was the substitution of one carbon atom of the A-, B-, C-or D-rings of the steroid framework by a heteroatom, specially nitrogen, leading to the discovery of potent inhibitors of human 5a-R such as 4-azasteroids, 6-azasteroids and 10-azasteroids [7,8]. The 4-azasteroid finasteride (Fig.…”

Section: Introductionmentioning

confidence: 99%

New steroidal 17β-carboxy derivatives present anti-5α-reductase activity and anti-proliferative effects in a human androgen-responsive prostate cancer cell line

et al. 2013

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a b s t r a c tThe androgens testosterone (T) and dihydrotestosterone (DHT), besides playing an important role in prostate development and growth, are also responsible for the development and progression of benign prostate hyperplasia (BPH) and prostate cancer. Therefore, the actions of these hormones can be antagonized by preventing the irreversible conversion of T into DHT by inhibiting 5a-reductase (5a-R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5a-reductase inhibitors (RIs). Steroidal RIs, finasteride and dutasteride, are used in clinic for BPH treatment and were also proposed for chemoprevention of prostate cancer. Nevertheless, due to the increase in bone and muscle loss, impotency and occurrence of high-grade prostate tumours, it is important to seek for other potent and specific molecules with lower side effects. In the present work, we designed and synthesized steroids with the 3-keto-D 4 moiety in the A-ring, as in the 5a-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17b position. The inhibitory 5a-R activity, in human prostate microsomes, as well as the anti-proliferative effects of the most potent compounds, in a human androgen-responsive prostate cancer cell line (LNCaP cells), were investigated. Our results showed that steroids 3, 4 and 5 are good RIs, which suggest that C-17b lipophylic amides favour 5a-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5a-R dependent-manner, similarly to finasteride.

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Selective non-steroidal inhibitors of 5α-reductase type 1

Cited by 54 publications

References 85 publications

Sexual dimorphism of growth plate prehypertrophic and hypertrophic chondrocytes in response to testosterone requires metabolism to dihydrotestosterone (DHT) by steroid 5‐alpha reductase type 1

Sexual dimorphism of growth plate prehypertrophic and hypertrophic chondrocytes in response to testosterone requires metabolism to dihydrotestosterone (DHT) by steroid 5‐alpha reductase type 1

5α- Reductase Inhibitors in Prostate Cancer: An Overview

New steroidal 17β-carboxy derivatives present anti-5α-reductase activity and anti-proliferative effects in a human androgen-responsive prostate cancer cell line

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