finasteride, Propecia
Finasteride: a slow-binding 5 alpha-reductase inhibitor.

Faller B, Farley D, Nick H.

Pharma Research Division, Ciba-Geigy Ltd., Basel, Switzerland.

A microsomal preparation of human prostatic tissue was used to study the kinetics of interaction of steroid 5 alpha-reductase with finasteride, a known 5 alpha-reductase inhibitor. This molecule has been reported to reversibly bind 5 alpha-reductase in a competitive manner to testosterone with a Ki value in the 10 nM range. The results presented in this paper show that enzyme-inhibitor complex formation does not take place instantaneously as assumed in previous studies. At neutral pH and 37 degrees C, the association of enzyme with inhibitor is governed by a rate constant, kon, of 2.7 x 10(5) M-1 s-1. This low kon value, in combination with the high energy of activation of the association reaction (150 kJ mol-1), indicates that the association process is not diffusion controlled and may proceed through intermediate steps. However, such an intermediate was not detected kinetically under the inhibitor concentrations investigated. We therefore conclude that the equilibrium dissociation constant, Ki*, for the initial binding of the enzyme to the inhibitor is higher than 1.5 x 10(7) M. Even at inhibitor concentrations as low as 1 nM, the reaction was completely displaced to the EI complex and no residual activity detected once the equilibrium was reached. Hence, the interaction between finasteride and 5 alpha-reductase can also be characterized by a very low overall equilibrium dissociation constant (Ki << 10(-9) M), at least 1 order of magnitude lower than previously reported values.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8389191&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effect of combination treatment with zanoterone (WIN 49596), a steroidal androgen receptor antagonist, and finasteride (MK-906), a steroidal 5 alpha-reductase inhibitor, on the prostate and testes of beagle dogs.

Juniewicz PE, Hoekstra SJ, Lemp BM, Barbolt TA, Devin JA, Gauthier E, Frenette G, Dube JY, Tremblay RR.

Department of Oncopharmacology, Sterling Winthrop Pharmaceuticals Research Division, Rensselaer, New York 12144.

The effects of the steroidal androgen receptor antagonist zanoterone (WIN 49596) and the steroidal 5 alpha-reductase inhibitor finasteride (MK-906) either alone or in combination on prostatic size, histomorphology, and biochemistry were determined in the intact male dog. Additionally, the effects of treatment with zanoterone and/or finasteride on testicular size, serum testosterone and LH levels, and spermatogenesis were determined in the same dogs. Daily oral treatment for 16 weeks with either zanoterone alone at 10 mg/kg.day or finasteride alone at 1.0 mg/kg.day reduced (P < 0.05) the size of the prostate, resulted in mild to moderate diffuse glandular atrophy of the prostate, and decreased prostatic DNA and prostatic arginine esterase (the primary canine prostatic protein) levels compared to those in intact controls. These changes occurred with no effect on testicular weight, testicular histomorphology, daily sperm production, or serum LH levels. Serum testosterone concentrations were increased (P < 0.05) approximately 3-fold in the 10 mg/kg.day zanoterone treatment group compared to those in intact controls. Combination treatment of male dogs for 16 weeks with zanoterone (10 mg/kg.day) plus finasteride (1.0 mg/kg.day) orally also reduced (P < 0.05) prostate size, resulted in moderate to marked diffuse prostatic glandular atrophy, and decreased prostatic DNA and arginine esterase levels more than either drug alone, without affecting testicular size, testicular histomorphology, serum LH concentrations, or serum testosterone concentrations compared to those in intact controls. The effects of combination treatment with zanoterone and finasteride on prostatic size; histomorphology; and DNA, arginine esterase protein, and arginine esterase mRNA levels were similar to those observed in castrate controls. In addition, in situ estimates of prostatic size using transrectal ultrasonography indicated that the median time to 70% prostatic regression in dogs administered combination zanoterone plus finasteride was similar to that in castrate controls (9.6 and 9.3 weeks, respectively), indicating that the combination was more effective in causing prostatic regression than either drug alone. Finally, at the dosages used, no adverse effects of combination treatment with zanoterone plus finasteride on testicular or other major body organ weights were observed. Based on these results, combination therapy using zanoterone and finasteride for the treatment of human androgen-dependent disorders such as benign prostatic hyperplasia and prostate cancer has potential utility.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8393778&dopt=Abstract finasteride Propecia



finasteride, Propecia
Characterization of Chinese hamster ovary cell lines expressing human steroid 5 alpha-reductase isozymes.

Thigpen AE, Cala KM, Russell DW.

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.

Membrane-bound isozymes of steroid 5 alpha-reductase, designated 1 and 2, synthesize the potent androgen, dihydrotestosterone. Isozyme 1 has an alkaline pH optimum (7.0-8.5), whereas isozyme 2 has an acidic pH optimum (5.0). To gain insight into this enigmatic difference, Chinese hamster ovarian cell lines expressing the human 5 alpha-reductase isozymes were established. The half-lives of both proteins are > 30 h and are not altered by the 4-azasteroid inhibitors finasteride and 17 beta-(N,N,-diethyl)carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one. Nanomolar concentrations of finasteride block immunoprecipitation of isozyme 2 by antipeptide antibodies, which suggests that drug binding alters protein conformation. In contrast, finasteride (50 microM) has no effect on immunoprecipitation of isozyme 1. Both isozymes are localized to the endoplasmic reticulum by immunocytochemistry and have their carboxyl termini exposed to the cytoplasm. In cell lysates, isozyme 2 exhibits a Vmax at pH 5.0 but has a higher substrate affinity at neutral pH. In intact and permeabilized cells, isozyme 2 has an apparent substrate Km similar to that determined in cell lysates at neutral pH. The results suggest that isozyme 2 is more efficient at neutral pH and that the acidic pH optimum determined in lysates is a consequence of cell lysis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8394341&dopt=Abstract finasteride Propecia



finasteride, Propecia
Finasteride blocks progesterone synthesis in MA-10 Leydig tumor cells.

Freeman DA, Gocze PM, Porpaczy Z.

Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104.

The 5 alpha-reductase inhibitor, finasteride, inhibits progesterone synthesis in the MA-10 Leydig tumor cells. Inhibition is dose-dependent with half maximal inhibition occurring at 10 ng/ml, a concentration significantly less than serum concentrations detected in finasteride-treated patients. Experiments to localize the site of inhibition by this compound revealed that the 3 beta-hydroxysteroid dehydrogenase delta 5-->delta 4 isomerase enzyme was not blocked by finasteride, but that cholesterol side-chain cleavage was inhibited. Thus, both dibutyryl-cAMP-stimulated and 22-hydroxycholesterol-stimulated steroidogenesis were inhibited by finasteride. This effect of finasteride to block cholesterol side-chain cleavage may be species-specific. Inhibition is readily detected in the mouse-derived MA-10 cells; however, human granulosa cell steroidogenesis is finasteride-insensitive while rat Leydig cell steroidogenesis is only minimally effected by finasteride.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8404636&dopt=Abstract finasteride Propecia



finasteride, Propecia
Finasteride inhibits 5 alpha-reductase activity in human dermal fibroblasts: prediction of its therapeutic application in androgen-related skin diseases.

Nguyen QH, Chen T, Wang X, Chen Y, Chien P.

Institute of Chemical Biology, University of San Francisco, CA 94117-1080, USA.

BACKGROUND. The potential role of finasteride in treating androgen related skin disorders was investigated. METHODS. Pooled human dermal fibroblasts were used to assess the effect of finasteride on the 5 alpha-reductase activity in skin tissue. Vmax and Km were estimated in the presence of 0, 10, and 200 nM finasteride. RESULTS. Vmax values remain constant near 1.20 pmol/mg protein/h in the presence of increasing concentrations of finasteride; however, apparent Km increases from 0.27 nM at 0 nM finasteride to 0.31 nM and 0.44 nM at 10 nM and 200 nM finasteride, respectively. This suggests that finasteride competes with testosterone and has a high affinity for same binding site of the 5 alpha-reductase enzyme. Apparent Ki was estimated at 282 nM, indicating that a high concentration of finasteride is required to significantly suppress the enzyme activity. CONCLUSIONS. This study confirms that finasteride inhibits the conversion of testosterone to dihydrotestosterone in human reticular dermal fibroblasts. Finasteride may have therapeutic potential in treating skin disorders influenced by the action of dihydrotestosterone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8537164&dopt=Abstract finasteride Propecia



finasteride, Propecia
Age-related changes in brain and pituitary 5 alpha-reductase with finasteride (Proscar) treatment.

Lephart ED.

Department of Zoology, Brigham Young University, Provo, UT 84602, USA.

Finasteride (Proscar), a 5 alpha-reductase inhibitor, was administered with or without 5 alpha-dihydrotestosterone (DHT) in juvenile (28), peripubertal (48), or young adult (68-day-old) male rats. Luteinizing hormone (LH) levels and ventral prostate (VP) weights monitored the efficacy of the treatments. For each postnatal day tested, LH hormone levels were not significantly altered by finasteride, suggesting that 5 alpha-reductase inhibition does not modulate LH in male rats using this protocol. Finasteride plus DHT treatment significantly decreased LH levels. Conversely, VP weights were significantly decreased in finasteride-treated animals while finasteride plus DHT treatment significantly increased VP values. Finasteride plus DHT treatment significantly decreased pituitary, but not brain, 5 alpha-reductase for each postnatal day tested. In finasteride-treated animals, hypothalamic and pituitary 5 alpha-reductase were significantly inhibited in young adult animals, whereas the activities were not altered in juvenile or peripubertal male rats. These data suggest that a different mechanism may regulate 5 alpha-reductase with the aging of the central nervous system and pituitary.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8544916&dopt=Abstract finasteride Propecia