Endocrine properties of the testosterone 5 alpha-reductase inhibitor turosteride (FCE 26073).
Turosteride was tested in a series of studies for its effect on 5 alpha-reductase and for its possible influence on other steroidogenic enzymes and on steroid receptors. The compound was found to inhibit human and rat prostatic 5 alpha-reductases with IC50 values of 55 and 53 nM, respectively, whereas it caused a less marked inhibition of the dog enzyme (IC50 2.2 microM). Turosteride showed no relevant effect on rat adrenal C20,22-desmolase (IC50 254 microM) and human placental aromatase (IC50 > 100 microM), and only at relatively high concentrations it caused inhibition of human placental 5-ene-3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) (IC50 2.5 microM). Turosteride was found to be a selective 5 alpha-reductase inhibitor showing no noteworthy binding to receptors for androgens (relative binding affinity, RBA, 0.004%), estrogens (< or = 0.005%), progesterone (< 0.005%), glucocorticoids (< 0.01%) and mineralocorticoids (< 0.03%). Its biochemical profile was similar to that of finasteride, whereas 4-MA (17 beta-N,N-diethyl-carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) was confirmed to be a non-selective 5 alpha-reductase inhibitor, showing a degree of binding affinity to the androgen receptor (RBA 0.1%) and a marked inhibition of 3 beta-HSD-I (IC50 32 nM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, turosteride reduced the ventral prostate and seminal vesicle growth promoting effect of TP, with IC50 values of approximately 5 and 6.7 mg/kg/day, whereas levator ani weight was unchanged. In comparison, 4-MA was approx. 3-fold less potent than turosteride in reducing the prostate and seminal vesicle weights and caused a marked reduction of levator ani weight, thus showing its unselectivity.
Di Salle
E
E
Laboratory of Endocrinology, R&D, Nerviano (MI), Italy.
Briatico
G
G
Giudici
D
D
Ornati
G
G
Panzeri
A
A
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D058891:5-alpha Reductase Inhibitors; D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D047072:Aromatase Inhibitors; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors; D004285:Dogs; D005260:Female; D018120:Finasteride / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D011467:Prostate / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D011817:Rabbits; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism; D012669:Seminal Vesicles / Q000254:growth & development; D013045:Species Specificity
D058891:5-alpha Reductase Inhibitors; D047072:Aromatase Inhibitors; D011987:Receptors, Steroid; D018120:Finasteride; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; C084634:turosteride