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Journal of Lipid Research, Vol. 24, 28-33, January 1983
Copyright © 1983 by Lipid Research, Inc.

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

Michael A. Schwartz and Simeon Margolis

Johns Hopkins University School of Medicine

This study examined the effects of various drugs and sterols on the rate of 7-hydroxycholesterol synthesis in isolated rat liver microsomes. Cholesterol 7-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-hydroxylase was also significantly inhibited by 7ßbeta;-hydroxycholesterol (38%) and 7-ketocholesterol (35%) at concentrations of 1µM, and by 10 µM 7-hydroxycholesterol (35%), 25-hydroxycholesterol (32%), and 5-cholenic acid-3ßbeta;-ol (27%). Two bile acids, cholate and lithocholate, as well as a geometric isomer of cholesterol, coprostanol, had little influence on 7-hydroxylase activity at concentrations of 10 µM. The inhibitory effect of metyrapone was additive with that of either 7ßbeta;-hydroxycholesterol or proadifen; the effects of 7ßbeta;-hydroxycholesterol and proadifen were not additive. These results suggest that proadifen and 7ßbeta;-hydroxycholesterol interact with the same enzyme site while metyrapone binds at a different location. Proadifen inhibited 7-hydroxylase irreversibly, while kinetic studies demonstrated noncompetitive inhibition by metyrapone (K_I = 0.55 mM) and competitive inhibition by 7ßbeta;-hydroxycholesterol (K_I = 2.4 µM). The inhibition of 7-hydroxylase activity by metyrapone and aminoglutethimide, drugs used to manage patients with excessive cortisol production, suggests that such treatment may also alter bile acid synthesis.—Schwartz, M. A., and S. Margolis. Effects of drugs and sterols on cholesterol 7-hydroxylase activity in rat liver microsomes.

Supplementary key words proadifen • metyrapone • aminoglutethimide • ascorbic acid • 7-hydroxycholesterol • 7ßbeta;-hydroxycholesterol • 7-keto-cholesterol • 25-hydroxycholesterol • 5-cholenic acid-3ßbeta;-ol

Submitted on January 18, 1982
Revised on August 10, 1982

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