LY191704: a selective, nonsteroidal inhibitor of human steroid 5 alpha-reductase type 1
Autor: | Nancy B. Stamm, David W. Russell, Blake Lee Neubauer, Stefan Andersson, Loretta Ames Mcquaid, James E. Audia, Richard E. Toomey, Kenneth Steven Hirsch, Pam Pennington, Charles David Jones |
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Rok vydání: | 1993 |
Předmět: |
Male
medicine.medical_specialty Quinolones Biology Transfection Isozyme Cell Line 5-alpha Reductase Inhibitors 3-Oxo-5-alpha-Steroid 4-Dehydrogenase Internal medicine medicine Animals Humans Testosterone Skin Multidisciplinary COS cells Finasteride Prostate Biological activity Hyperplasia medicine.disease Rats Isoenzymes Kinetics Endocrinology Cell culture Enzyme inhibitor Azasteroids Dihydrotestosterone biology.protein Androstenes Research Article medicine.drug |
Zdroj: | Proceedings of the National Academy of Sciences. 90:5277-5281 |
ISSN: | 1091-6490 0027-8424 |
Popis: | 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 5 alpha-reductase [5 alpha-reductase; 3-oxo-5 alpha-steroid delta 4-dehydrogenase; 3-oxo-5 alpha-steroid:(acceptor) delta 4-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 5 alpha-reductase type 2 have been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of 5 alpha-reductase type 1, LY191704 (8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo[f]quinol in-3(2H)-one). This compound was identified based on its capacity to inhibit 5 alpha-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 5 alpha-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5 alpha-reductases expressed from transfected cDNAs in simian COS cells indicates that LY191704 is a specific noncompetitive inhibitor of the human 5 alpha-reductase type 1. Taken together, the results suggest that prostate cells have the capacity to express both 5 alpha-reductase isozymes and that LY191704 may be useful in treatment of human endocrine disorders associated with overproduction of DHT by 5 alpha-reductase type 1. |
Databáze: | OpenAIRE |
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