High-dose ketoconazole has been used to control hypercortisolism in Cushing disease when surgery fails. Its antiglucocorticoid action is explained by:

• A Competitive blockade of the glucocorticoid receptor
• B Enhanced hepatic catabolism of cortisol through induction of CYP3A4
• C Inhibition of multiple cytochrome P450 enzymes required for adrenal steroidogenesis ✓
• D Blockade of ACTH receptors on the zona fasciculata

Explanation

At high doses ketoconazole inhibits several steroidogenic P450 enzymes, including cholesterol side chain cleavage enzyme (CYP11A1) and CYP17A1, reducing synthesis of cortisol and androgens by the adrenal cortex. This contrasts with mifepristone, which acts at the receptor level, making option A the tempting distractor. Ketoconazole is a CYP3A4 inhibitor, not an inducer, and it acts enzymatically rather than on the ACTH receptor. Hepatotoxicity limits its use.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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