In vivo assay for conversion of testosterone to dihydrotestosterone by rat prostatic steroid 5 alpha-reductase and comparison of two inhibitors.
An in vivo assay for steroid 5 alpha-reductase in rat ventral prostate has been developed and used to compare the inhibitory activity of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) and 6-methylene-4-pregnene-3,20-dione (LY207320). Immature rats (70-80 g) received test compounds 30 min prior to s.c. injection of [3H]-T. The rats were sacrificed 30 min later and the ventral prostates were analyzed for [3H]-T metabolites. Intraprostatic [3H]-T and [3H]-DHT reached peak levels within 5 min after injection of [3H]-T and declined to about 25% of peak levels after 2 hr. 4-MA was a very potent inhibitor of [3H]-DHT formation with an estimated IC50 of 0.2 mg/kg. LY207320, an inhibitor of 5 alpha-reductase in vitro, was weakly active in vivo and did not achieve greater than 45% inhibition at high doses (greater than 200 mg/kg, s.c.). Tissue uptake of [3H]-T was also inhibited by LY207320, which may contribute to its inhibitory activity on accessory sex organ growth in the rat.
Toomey
R E
RE
Endocrine Research, Lilly Research Labs, Indianapolis, Indiana 46285.
Goode
R L
RL
Petrow
V
V
Neubauer
B L
BL
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D011374:Progesterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011467:Prostate / Q000201:enzymology*; D051381:Rats; D011916:Rats, Inbred F344; D013739:Testosterone / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D001378:Azasteroids; D013196:Dihydrotestosterone; D014316:Tritium; C036790:6-methylene-4-pregnene-3,20-dione; D013739:Testosterone; D011374:Progesterone; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase