Reversible long-term toxicity of epristeride in beagle dogs

Epristeride (17 beta-N-t-butylcarboxamide-androst-3, 5-diene-3-carboxylic a cid) is an uncompetitive inhibitor of steroid 5 alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT), and has been show n to retard the growth of hyperplastic prostates, The objective of the curr ent investigation was to research the toxic effects of epristeride and to d emonstrate its reversible. In the experiment, 18 beagle dogs (male, about 6 months old) were used and divided into six groups, with each group contain ing three dogs. Groups A and B were placebo-treated for 180 and 240 days, G roups C and D were treated with 10 and 100 mg/kg epristeride for 180 days, and Groups E and F were treated with 10 and 100 mg/kg epristeride for 180 d ays and then were placebo-treated for 60 days (total 240 days), respectivel y. Routine analyses were performed at the 1st, 30th, 90th, 180th, and 240th days, and the dogs were autopsied at the 180th or 240th day for systemic e xamination and measured for relative DNA content in single prostatic epithe lial cells, Each prostate was fixed with 4% Formalin, embedded in paraffin, sectioned at 6 mu m, and immunohistochemically stained for assaying the re lative content (transmittance) of prostatic specific antigen (PSA) and DHT (%) with a microspectrophotometer at 650-nm wavelength, The results were th at 180 days of toxicity with epristeride (100 mg/kg) on interstitial cells of testes and DNA in prostatic epithelial cells couldn't reverse during 60 days of convalescence and that the DHT and PSA levels in the gland, the vol ume of the gland, glandular epithelial cell height, and acinar luminal area could reverse to normal during the same convalescence. To our knowledge th is is the first study documenting the toxicity of epristeride, It is necess ary to further study the molecular and clinical toxicity of epristeride. (C ) 1999 Academic Press.