Ketoconazole, an antifungal agent, was historically used orally to control hypercortisolism in Cushing syndrome. Its steroid-lowering action results from:
- A Inhibition of adrenocortical cytochrome P450 enzymes including cholesterol side chain cleavage and 11-beta hydroxylase ✓
- B Blockade of the glucocorticoid receptor in target tissues
- C Enhanced hepatic metabolism of cortisol through CYP3A4 induction
- D Suppression of pituitary ACTH release via somatostatin receptor activation
Correct answer: A. Inhibition of adrenocortical cytochrome P450 enzymes including cholesterol side chain cleavage and 11-beta hydroxylase
Explanation
Ketoconazole directly inhibits several cytochrome P450 dependent steps in adrenal steroidogenesis, notably cholesterol side chain cleavage (CYP11B1), 17-alpha hydroxylase and 11-beta hydroxylase, thereby reducing cortisol synthesis irrespective of the cause of hypercortisolism. It does not touch the glucocorticoid receptor, which is mifepristone's site of action, nor does it induce CYP3B4; in fact ketoconazole is a CYP3B4 inhibitor. Hepatotoxicity limits its current use for this indication.
Reference: Katzung Basic and Clinical Pharmacology, 15th ed.
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