Rapid improvement in patients with Cushing's syndrome (10, 11) and increased hydrocortisone dose requirement during mitotane therapy (1) may thus be explained by decreased bioavailability of oral cortisol due to rapid conversion by CYP3A4 in the liver, perhaps during a first pass after adsorption from the gut. The gene discussed is CYP3A4; the disease is Cushing syndrome due to macronodular adrenal hyperplasia.