Pharmacologic stimulation of Cytochrome P450 46A1 and Cerebral Cholesterol Turnover in Mice

Background: Elevation of cerebral cholesterol turnover in mice due to increased CYP46A1 expression has palliative effects on hallmarks of Alzheimer disease. Results: CYP46A1 could also be activated post-translationally by drugs in vitro and in vivo. Conclusion: CYP46A1 is a viable therapeutic target. Significance: Pharmacologic stimulation of CYP46A1 and cerebral cholesterol turnover may lead to new therapeutic strategies for the treatment of brain disorders. Cytochrome P450 46A1 (CYP46A1) is a brain-specific cholesterol 24-hydroxylase responsible for the majority of cholesterol elimination from the brain. Genetically increased CYP46A1 expression in mice leads to improved cognition and decreases manifestations of Alzheimer disease. We found that four pharmaceuticals (efavirenz (EFV), acetaminophen, mirtazapine, and galantamine) prescribed for indications unrelated to cholesterol maintenance increased CYP46A1 activity in vitro. We then evaluated the anti-HIV medication EFV for the mode of interaction with CYP46A1 and the effect on mice. We propose a model for CYP46A1 activation by EFV and show that EFV enhanced CYP46A1 activity and cerebral cholesterol turnover in animals with no effect on the levels of brain cholesterol. The doses of EFV administered to mice and required for the stimulation of their cerebral cholesterol turnover are a hundred times lower than those prescribed to HIV patients. At such small doses, EFV may be devoid of adverse effects elicited by high drug concentrations. CYP46A1 could be a novel therapeutic target and a tool to further investigate the physiological and medical significance of cerebral cholesterol turnover.