Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents

Joel J. Sheets, J. Ian Mason, Carol A. Wise, Ronald W. Estabrook

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)487-491
Number of pages5
JournalBiochemical Pharmacology
Volume35
Issue number3
DOIs
StatePublished - Feb 1 1986

Fingerprint

Steroid Hydroxylases
Liver
Cytochrome P-450 Enzyme System
Rats
Androstenedione
Liver Microsomes
Mixed Function Oxygenases
Oxidoreductases
Clotrimazole
Miconazole
Ketoconazole
Steroids
Metabolism
imidazole

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents. / Sheets, Joel J.; Mason, J. Ian; Wise, Carol A.; Estabrook, Ronald W.

In: Biochemical Pharmacology, Vol. 35, No. 3, 01.02.1986, p. 487-491.

Research output: Contribution to journalArticle

@article{debdf8d0014a469588e1eea426cfe389,
title = "Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents",
abstract = "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.",
author = "Sheets, {Joel J.} and Mason, {J. Ian} and Wise, {Carol A.} and Estabrook, {Ronald W.}",
year = "1986",
month = "2",
day = "1",
doi = "10.1016/0006-2952(86)90224-8",
language = "English (US)",
volume = "35",
pages = "487--491",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "3",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=0022586787&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0022586787&partnerID=8YFLogxK

U2 - 10.1016/0006-2952(86)90224-8

DO - 10.1016/0006-2952(86)90224-8

M3 - Article

C2 - 3947383

AN - SCOPUS:0022586787

VL - 35

SP - 487

EP - 491

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 3

ER -