TY - JOUR
T1 - Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents
AU - Sheets, Joel J.
AU - Mason, J. Ian
AU - Wise, Carol A.
AU - Estabrook, Ronald W.
N1 - Funding Information:
* Supported, in part, by Grants NIGMS 16488 and CA-30253 from the National Institutes of Health, USPHS. J.J.S. was supported, in part, by a USPHS National Research Service Award (l-F32-HD-06596-01) and a Postdoctoral Fellowship from the Chilton Foundation. $ Address correspondence to: Dr. Joel Sheets, Department of Biochemistry, University of Texas Health Science Center, 5323 Harry Hines Blvd., Dallas, TX 75235.
PY - 1986/2/1
Y1 - 1986/2/1
N2 - The imidazole antimycotic agents ketoconazole, miconazole and clotrimazole were tested for their abilities to inhibit the reactions involved in the oxidative metabolism of androst-4-ene-3,17-dione by rat liver microsomal cytochromes P-450. All three compounds were found to function as potent inhibitors of steroid hydroxylase reactions, producing 50% inhibition of 6β-, 16β-, and 16α-hydroxylase activities at concentrations between 10-7 and K-5M. The antimycotic agents, when added to liver microsomes, bound to cytochrome P-450 with high affinity to produce a "type II" spectral complex. These agents showed differential inhibition of the various steroid hydroxylases and were found not to affect the activities of the liver microsomal steroid 5α-reductase or the androst-4-ene-3,17-dione 17-oxidoreductase. The results presented demonstrate an interaction of these imidazole antimycotic agents with the various cytochromes P-450 of liver microsomes, resulting in selective inhibition of monooxygenase activity.
AB - The imidazole antimycotic agents ketoconazole, miconazole and clotrimazole were tested for their abilities to inhibit the reactions involved in the oxidative metabolism of androst-4-ene-3,17-dione by rat liver microsomal cytochromes P-450. All three compounds were found to function as potent inhibitors of steroid hydroxylase reactions, producing 50% inhibition of 6β-, 16β-, and 16α-hydroxylase activities at concentrations between 10-7 and K-5M. The antimycotic agents, when added to liver microsomes, bound to cytochrome P-450 with high affinity to produce a "type II" spectral complex. These agents showed differential inhibition of the various steroid hydroxylases and were found not to affect the activities of the liver microsomal steroid 5α-reductase or the androst-4-ene-3,17-dione 17-oxidoreductase. The results presented demonstrate an interaction of these imidazole antimycotic agents with the various cytochromes P-450 of liver microsomes, resulting in selective inhibition of monooxygenase activity.
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U2 - 10.1016/0006-2952(86)90224-8
DO - 10.1016/0006-2952(86)90224-8
M3 - Article
C2 - 3947383
AN - SCOPUS:0022586787
SN - 0006-2952
VL - 35
SP - 487
EP - 491
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 3
ER -