FK143, a novel nonsteroidal inhibitor of steroid 5α-reductase: (2) In vivo effects on rat and dog prostates

Hirosumi, Jiro; Numata, Osamu; Chida, Noboru; Inami, Masamichi; Fagan, TC; Sawada, Kozo; Shigematsu, S; Kojo, Hitoshi; Notsu, Yoshitada; Okuhara, Masakuni

doi:10.1016/0960-0760(94)00188-r

Cited by 26 publications

(15 citation statements)

References 36 publications

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“…The T and DHT levels in the male accessory organs, prostate, and seminal vesicles were compared immediately after castration. DHT was dominant in 2 organs as previously reported, and the T and DHT levels were similar to those in previous reports (Damassa and Gustafson, 1988; Hirosumi et al, 1995; Nakayama et al, 1997). The T/DHT ratio in the prostate was lower than in the seminal vesicles.…”

Section: Discussionsupporting

confidence: 91%

“…Study of androgen dynamics is important in investigating the causes of these disorders. There have been several reports of androgen content in serum and tissues (Hirosumi et al, 1995; Nakayama et al, 1997; Gottreich et al, 2000; Dohle et al, 2003; Torres et al, 2003). However, accurate measurement of tissue androgen content is difficult because of abundant impurities.…”

mentioning

confidence: 99%

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Changes in Testosterone and Dihydrotestosterone Levels in Male Rat Accessory Sex Organs, Serum, and Seminal Fluid After Castration: Establishment of a New Highly Sensitive Simultaneous Androgen Measurement Method

Kashiwagi

Shibata

Ono

et al. 2005

Journal of Andrology

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ABSTRACT:It is known that abnormal androgen dynamics in the tissues is a cause of androgen-dependent disorders. Investigation of tissue androgen levels could provide a clue to the elucidation of disorders. However, it is difficult to measure a trace amount of androgen in the tissues. We established a highly sensitive simultaneous quantification method of testosterone and dihydrotestosterone (DHT), which play the most important roles in the body among androgenic steroids in trace amounts, and investigated time course changes in testosterone and DHT levels in male accessory sex organs, serum, and seminal fluid after castration in rat models. In addition, changes in the testosterone/DHT ratio of male accessory sex organs and seminal fluid were observed. The simultaneous testosterone and DHT measurement method established by us was validated. Intra-assay variation and interassay precision and accuracy were all within Ϯ20%, and the quantification limits of testosterone and DHT were both 15.6 pg/g. With the use of this method, the testosterone and DHT levels in the prostate, seminal vesicles, and serum immediately after castration were similar to those previously reported. The testosterone and DHT levels were 350 pg/g and 605 pg/g, respectively; which showed dominance of DHT in seminal fluid, although it was not as marked as that in the male accessory sex organs. Androgens decreased with time after castration in the accessory sex organs, serum, and seminal fluid. In the prostate and seminal vesicles, testosterone and DHT decreased to about 50% and about 2% of the normal levels, respectively, 72 hours after castration. The serum levels were under the quantification limits 6 hours after castration and thereafter. In seminal fluid, the testosterone and DHT levels decreased to 49% and 35% of normal levels, respectively, 72 hours after castration. The testosterone/DHT ratio in the male accessory sex organs was lower in the prostate (0.06) than in the seminal vesicles (0.13) immediately after castration. In the seminal fluid, changes in the ratio were small compared with those in the accessory sex organs and serum. These results showed that our method was capable of measuring testosterone and DHT in very small amounts of samples such as prostate biopsy specimens, and it might provide a clue to the elucidation of the pathology of androgen-dependent disorders.Key words: LC-MS/MS, hormone, prostate, seminal vesicles. J Androl 2005;26:586-591A ndrogen is an important male steroid hormone that regulates metabolism in many organs, and its effect is obvious in male sex organs. There are 4 androgens, and testosterone (T) synthesized by Leydig cells in the testis mainly presents in the circulation. Another dominant androgen is dihydrotestosterone (DHT) synthesized from T by 5-alpha reductase in the target organs. T and DHT play an important role in sexuality differentiation and development of secondary sex characteristics. In addition to T and DHT, androgens with very weak action, dehydroepiandrosterone (DHEA) and androstenedione (4...

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Changes in Testosterone and Dihydrotestosterone Levels in Male Rat Accessory Sex Organs, Serum, and Seminal Fluid After Castration: Establishment of a New Highly Sensitive Simultaneous Androgen Measurement Method

Kashiwagi

Shibata

Ono

et al. 2005

Journal of Andrology

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“…These findings, together with our recent report that Z-350 does not reduce prostatic growth induced by dihydrotestosterone in castrated rats (17), indicate that Z-350 reduces prostatic weight only by inhibition of 5a-R, without affecting serum hormonal levels. This result is in agreement with those for other 5a-R inhibitors (19,31).…”

Section: Discussionsupporting

confidence: 82%

“…Effects in normal and 17b-estradiol-treated female rats Z-350 (10 -100 mg/ kg) were given orally once a day for 4 days to 4-week-old normal female rats and female rats treated with 17b-estradiol (100 mg / animal subcutaneously) (19). The uterus was removed and weighed as above.…”

Section: Effects In Castrated Male Ratsmentioning

confidence: 99%

Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

Fukuda

Fukuta

Higashino

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-We examined the hormonal effects of Z-350, (S)-4-[3-(4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy}benzoyl)indole-1-yl]butyric acid hydrochloride, which has both a1-adrenoceptor blocking activity and steroid 5a-reductase inhibitory activity, in male and female rats. Z-350 administered orally for 14 days at a dose of 30 mg/ kg to normal male rats significantly reduced the weight of the prostate and seminal vesicles without affecting the weight of the testis, epididymis, adrenals, kidney or liver. Prostatic levels of dihydrotestosterone decreased dose-dependently, with a slight increase in the level of testosterone at a Z-350 dose of 100 mg/ kg. We observed no effects on the weight of the prostate in castrated rats or on the weight of the uterus in normal or 17b-estradiol-treated female rats. These results suggest that Z-350 inhibits prostatic growth via inhibition of steroid 5-reductase without other hormonal effects.Keywords: Z-350, Steroid 5a-reductase, Benign prostatic hyperplasia, Testosterone, Dihydrotestosterone Benign prostatic hyperplasia (BPH), which is a common disorder in aging men, is associated with growth of prostatic glandular and stromal elements. BPH causes symptoms in the lower urinary tract and reduces quality of life.The lower urinary tract symptoms caused by BPH are attributed to two main components: a dynamic component involving excessive contraction of prostatic smooth muscle mediated by a 1-adrenoceptors (1 -4) and a static component involving obstruction of the urethra by the enlarged prostate (5). a1-Adrenoceptor blockers (6 -10) represent a palliative approach to therapy for lower urinary tract symptoms caused by BPH and are effective in alleviating dynamic obstruction. On the other hand, anti-androgens can improve static obstruction by reducing prostatic mass, although they have adverse effects on sexual function, including impotence and decreased libido, which is caused by plasma testosterone deprivation (5).Steroid 5a-reductase (EC 1.3.1.22; 5a-R), a rate-limiting enzyme that converts testosterone to the potent androgen dihydrotestosterone, plays a critical role in prostatic growth (11). Finasteride is a specific 5a-R inhibitor that can reduce prostate volume with fewer adverse effects on sexual function than anti-androgens (12 -15), and it has already been approved for clinical use in the US and Europe.On the basis of the concept that combined activity (i.e., a 1-adrenoceptor blocking and 5a-R inhibition) may be more beneficial for the treatment of BPH than each activity alone, we recently reported the pharmacological profile of Z-350, which possesses a1-adrenoceptor blocking and 5a-R inhibitory activity, in vitro (16) and in vivo (17). Z-350 inhibited rat prostatic 5a-R in a non-competitive manner and prevented testosterone-induced re-growth of the prostate in castrated rats.In the present study, we investigated the effects of Z-350 on the weight of the testis, epididymis, adrenal gland and other organs in normal male rats to evaluate the hormonal eff...

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“…Clinical studies in humans are reportedly underway, although recent results are not available (23,24). There are a host of other inhibitors in this structural class including inhibitors from Fujisawa (FK-143) (25)(26)(27)(28)(29), Kyowa Hakko Kogyo (KF18678) (30), and Pfizer (31,32).…”

Section: Dihydrotestosterone (Dht)mentioning

confidence: 99%

Steroid 5α-Reductase: Comparative Study of Mechanism of Inhibition by Nonsteroids ONO-3805 and LY191704

Harris

Ellsworth

Witzel

et al. 1996

Bioorganic Chemistry

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FK143, a novel nonsteroidal inhibitor of steroid 5α-reductase: (2) In vivo effects on rat and dog prostates

Cited by 26 publications

References 36 publications

Changes in Testosterone and Dihydrotestosterone Levels in Male Rat Accessory Sex Organs, Serum, and Seminal Fluid After Castration: Establishment of a New Highly Sensitive Simultaneous Androgen Measurement Method

Changes in Testosterone and Dihydrotestosterone Levels in Male Rat Accessory Sex Organs, Serum, and Seminal Fluid After Castration: Establishment of a New Highly Sensitive Simultaneous Androgen Measurement Method

Hormonal Effects of Z-350, Possessing Steroid 5 a-Reductase Inhibitory and a ι-Adrenoceptor Antagonistic Actions, in the Rat

Steroid 5α-Reductase: Comparative Study of Mechanism of Inhibition by Nonsteroids ONO-3805 and LY191704

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