Abstract 058: Deoxycorticosterone-induced Hypertension Caused by Fluconazole

Abstract

Deoxycorticosterone (DOC), a steroid precursor of aldosterone, constitutes an endogenous mineralocorticoid receptor agonist. Exogenous DOC produces a well-established animal model of mineralocorticoid-induced salt-dependent hypertension (HTN), but, except for rare cases of congenital adrenal hyperplasia with pediatric HTN due to CYP11 β1 (11 β hydroxylase, P450c11 β ) deficiency, DOC is rarely considered a cause of clinical hypertension (HTN). We recently suspected DOC as the novel mechanism of severe low-renin HTN (blood pressure, BP 220/150 mmHg, plasma renin activity 0.21 ng/mL/hour) that developed de novo in a 47- year old African American man with previously normal BP (118/74) during treatment of disseminated coccidiodomycosis with high-dose fluconazole, which blocks P450 enzymes in the fungal cell wall. To determine if the fluconazole also inhibited human CYP11β1, the adrenal P450 enzyme that converts DOC to corticosterone, we performed a comprehensive adrenal steroid panel on the patient’s serum using mass spectrometry. During the HTN, his serum [DOC] was 24-times the upper limit of normal (354 vs. <15 ng/dL), while corticosterone was low and aldosterone was undetectable. Both the HTN and the high DOC were caused by fluconazole, because they normalized after treatment ended. We then proved that fluconazole causes dose-dependent inhibition of CYP11β1 in vitro by transfecting a mammalian (hamster V79) cell line with human CYP11 β 1 and incubating the cells with DOC. The observed IC50—10 μM— is certainly less than the plasma [fluconazole] during oral high-dose therapy. From these data, we conclude that high-dose fluconazole inhibits DOC conversion by human CYP11β1, causing in this adult patient an acquired form of severe DOC-induced HTN. Given the recent 10-fold increase in coccidiodomycosis cases in the United States and the marked propensity for disseminated disease in African American patients, BP should be monitored carefully during treatment with high-dose fluconazole. Additional case finding studies are warranted.