Effects of drugs and sterols on cholesterol 7 α-hydroxylase activity in rat liver microsomes

M. A. Schwartz, Simeon Margolis

Research output: Contribution to journalArticle

Abstract

This study examined the effects of various drugs and sterols on the rate 7 α-hydroxycholesterol synthesis in isolated rat liver microsomes. Cholesterol 7 α-hydroxylase activity was significantly inhibited by proadifen (98%), metyrapone (67%), and aminoglutethimide (45%) at concentrations of 1 mM and by ascorbic acid (40%) at a concentration of 10 mM. Cimetidine had no significant effect. The activity of cholesterol 7 α-hydroxylase was also significantly inhibited by 7 β-hydroxycholesterol (38%) and 7-ketocholesterol (35%) at concentrations of 1 μM, and by 10 μM 7α-hydroxycholesterol (35%), 25 α-hydroxycholesterol (32%), and 5-cholenic acid-3β-ol (27%). Two bile acids, cholate and lithocholate, as well as a geometric isomer of cholesterol, coprostanol, had little influence on 7 α-hydroxylase activity at concentrations of 10 μM. The inhibitory effect of metyrapone was additive with that of either 7 β-hydroxycholesterol or proadifen; the effects of 7 β-hydroxycholesterol and proadifen were not additive. These results suggest that proadifen and 7β-hydroxycholesterol interact with the same enzyme site while metyrapone binds at a different location. Proadifen inhbited 7 α-hydroxylase irreversibly, while kinetic studies demonstrated noncompetitive inhibition by metyrapone (K(I) = 0.55 mM) and competitive inhibition by 7 β-hydroxycholesterol (K(I) = 2.4 μM). The inhibition of 7 α-hydroxylase activity by metyrapone and aminoglutethimide, drugs used to manage patients with excessive cortisol production, suggest that such treatment may also alter bile acid synthesis.

Original languageEnglish (US)
Pages (from-to)28-33
Number of pages6
JournalJournal of Lipid Research
Volume24
Issue number1
StatePublished - 1983

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Cholesterol 7-alpha-Hydroxylase
Hydroxycholesterols
Liver Microsomes
Sterols
Proadifen
Liver
Metyrapone
Rats
Pharmaceutical Preparations
Mixed Function Oxygenases
Aminoglutethimide
Bile Acids and Salts
Cholestanol
Lithocholic Acid
Cholates
Cimetidine
Isomers
Ascorbic Acid
Hydrocortisone
Cholesterol

ASJC Scopus subject areas

  • Endocrinology

Cite this

Effects of drugs and sterols on cholesterol 7 α-hydroxylase activity in rat liver microsomes. / Schwartz, M. A.; Margolis, Simeon.

In: Journal of Lipid Research, Vol. 24, No. 1, 1983, p. 28-33.

Research output: Contribution to journalArticle

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