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Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans

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Serum 4β-hydroxycholesterol increases during fluconazole treatment.

Dieter Lütjohann¹, Frans Stellaard², Anja Kerksiek²

¹Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany. dieter.luetjohann@ukbonn.de.

European Journal of Clinical Pharmacology

|November 17, 2020

Summary

Fluconazole increases specific sterols and oxysterols in the blood, unlike other azole antifungals. This suggests a different effect on cholesterol metabolism and cytochrome P450 activity.

Keywords:

Antifungal Bile acid precursors Cholesterol metabolism Cholesterol synthesis Cytochrome P450 Oxysterols

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Cholesterol Efflux Assay

Cholesterol Efflux Assay

Published on: March 6, 2012

Area of Science:

Biochemistry
Pharmacology
Metabolism

Background:

Azole antifungal agents can affect cholesterol metabolism.
Ketoconazole and itraconazole reduce serum 4β-hydroxycholesterol, a marker for hepatic cytochrome P450 (CYP) 3A4 activity.
The effect of fluconazole on sterols and oxysterols is not well understood.

Purpose of the Study:

To investigate the effect of fluconazole on serum sterols and oxysterols in cholesterol metabolism.
To determine if the observed changes are a general side effect of azole antifungal agents.

Main Methods:

Prospective, double-blind, placebo-controlled, two-way crossover study with 17 healthy subjects.
Subjects received 400 mg fluconazole or placebo daily for 8 days.
Serum sterols and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring.

Main Results:

Fluconazole significantly increased serum R_lanosterol and R_24,25-dihydrolanosterol.
Serum cholesterol and downstream markers of hepatic cholesterol synthesis remained unaffected.
Serum R_4β-, R_24S-, and R_27-hydroxycholesterol levels increased significantly.

Conclusions:

Fluconazole inhibits lanosterol 14α-demethylation (CYP51A1) without reducing overall cholesterol synthesis.
Increased R_4β-hydroxycholesterol under fluconazole differs from ketoconazole and itraconazole effects.
Further studies are needed to elucidate the mechanism behind increased R_4β-hydroxycholesterol and fluconazole's impact on CYP3A4 activity.