Inhibition of human adrenal steroidogenic enzymes in vitro by imidazole drugs including ketoconazole.
The effect of several imidazole containing drugs including keto on human adrenal 17 alpha-hydroxylase, 17,20-lyase, 21-hydroxylase, 11 beta-hydroxylase and 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) activities was studied in vitro. The order of decreasing inhibitory potency as determined from ID50 values for both 17 alpha-hydroxylase (ID50 values ranged from 1.13-4.17 mumol/l) and 17,20-lyase (0.57-1.95 mumol/l) activities was: bifon greater than clot greater than keto greater than micon greater than econ greater than isocon greater than tiocon. Using [3H]progesterone (5.50-12.25 mumol/l) as the substrate for the 21-hydroxylase activity the order of decreasing inhibitory potency was: clot greater than bifon greater than isocon greater than micon greater than tiocon greater than econ greater than tiocon greater than keto. For the 11 beta-hydroxylation of [3H]deoxycortisol (1.48-2.34 mumol/l) the order of decreasing inhibitory potency was keto greater than bifon greater than clot greater than micon greater than econ greater than isocon greater than tiocon. The cytochrome P-450 dependent enzyme most sensitive to inhibition was 17,20-lyase and the least sensitive was 21-hydroxylase whereas the imidazole drugs were without effect on the cytochrome P-450 independent 3 beta-HSD-I activity. In agreement with previous results a common structural feature of the imidazole drugs having an inhibitory effect was the presence of aromatic rings on the N-1 substituent of the imidazole ring.
Ayub
M
M
Department of Chemical Pathology, University of Leeds, England.
Levell
M J
MJ
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000311:Adrenal Glands / Q000201:enzymology*; D000368:Aged; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D011375:Progesterone Reductase / Q000037:antagonists & inhibitors*; D013254:Steroid 17-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009097:Multienzyme Complexes; D015096:3-Hydroxysteroid Dehydrogenases; D011375:Progesterone Reductase; D013250:Steroid Hydroxylases; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases; D007535:Isomerases; D013251:Steroid Isomerases; D007654:Ketoconazole