Cytochrome P450 enzymes 46A1 (CYP46A1) and 27A1 (CYP27A1) act on the same substrate, cholesterol, but metabolize it to different products, 24-hydroxycholesterol (24HC) and 27-hydroxycholesterol (27HC), respectively. CYP46A1 is mainly expressed in neural tissues, the brain and retina, whereas CYP27A1 is ubiquitous. Enzymatic reactions catalyzed by CYPs 46A1 and 27A1 serve two main purposes: cholesterol elimination and cellular regulation. 24HC and 27HC (also called oxysterols) represent transport forms of cholesterol to the liver, and are also regulatory molecules modulating a variety of cellular processes. Animal studies demonstrate that elevated 24HC levels enhance memory and learning and diminish the development of amyloid plaques, a hallmark of Alzheimer's disease (AD). Elevated 27HC levels, however, are deleterious in post-menopausal women as indicated by epidemiologic studies showing that this population group has increased risk of coronary heart disease and the progression of estrogen-receptor positive breast cancer. The involvement of 24HC and 27HC in normal and pathological processes make CYP46A1 and CYP27A1, which produce these oxysterols, potential targets for therapeutic treatments. The challenge is that enzymatic activity of CYP46A1 should be stimulated, which is difficult to accomplish post-translationally, whereas enzymatic activity CYP27A1 should be inhibited but only partially. We found a number of drugs on the US market that have unanticipated binding to either CYP46A1 or CYP27A1 and modulate the activities of these P450s in mice. Pharmacologic stimulation of CYP46A1 has never been accomplished before and opened a totally new area of investigation, which we began to develop. We selected efavirenz (an anti-HIV drug), which at tiny doses activates CYP46A1 and cholesterol turnover in mouse brain, and began drug treatments of 5XFAD mice, a model of AD. We also tested CYP46A1 for activation by endogenous compounds, such as neurotransmitters, and discovered that some of them activate CYP46A1 in vitro. Our pilot investigation of CYP27A1 demonstrated that this P450 is a druggable target and can partially be inhibited by some of the marketed medications both in vitro and in mice. In this competing renewal we propose to continue our ongoing studies.
The Specific Aims are: 1) to ascertain the effects of long-term efavirenz treatments on cholesterol homeostasis and pathological processes in the brain of a mouse model of AD; 2) to generate a model of CYP46A1 activation by neuroactive compounds; 3) to identify more drugs on the market that partially inhibit CYP27A1. We will obtain principally new information about the role of cholesterol metabolism in normal and disease-affected brain and whether efavirenz should be tested on humans as a new anti-AD drug. We will also identify additional medications for potential off label use in post-menopausal women with atherosclerosis or breast cancer. Collectively, the proposed research will significantly advance our understanding of the role of cholesterol metabolism in different organs and how to control this process pharmacologically.
|Lam, Morrie; Mast, Natalia; Pikuleva, Irina A (2018) Drugs and Scaffold That Inhibit Cytochrome P450 27A1 In Vitro and In Vivo. Mol Pharmacol 93:101-108|
|Mast, Natalia; Anderson, Kyle W; Johnson, Kevin M et al. (2017) In vitro cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds. J Biol Chem 292:12934-12946|
|Mast, Natalia; Anderson, Kyle W; Lin, Joseph B et al. (2017) Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum. J Biol Chem 292:4913-4924|
|Mast, Natalia; Lin, Joseph B; Anderson, Kyle W et al. (2017) Transcriptional and post-translational changes in the brain of mice deficient in cholesterol removal mediated by cytochrome P450 46A1 (CYP46A1). PLoS One 12:e0187168|
|Mast, Natalia; Saadane, Aicha; Valencia-Olvera, Ana et al. (2017) Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease. Neuropharmacology 123:465-476|
|Saeed, Ahmed A; Edström, Erik; Pikuleva, Irina et al. (2017) On the importance of albumin binding for the flux of 7?-hydroxy-3-oxo-4-cholestenoic acid in the brain. J Lipid Res 58:455-459|
|Anderson, Kyle W; Mast, Natalia; Hudgens, Jeffrey W et al. (2016) Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity. J Biol Chem 291:11876-86|
|Anderson, Kyle W; Chen, Junjun; Wang, Meiyao et al. (2015) Quantification of histone deacetylase isoforms in human frontal cortex, human retina, and mouse brain. PLoS One 10:e0126592|
|Anderson, Kyle W; Mast, Natalia; Pikuleva, Irina A et al. (2015) Histone H3 Ser57 and Thr58 phosphorylation in the brain of 5XFAD mice. FEBS Open Bio 5:550-6|
|van Lier, Johan E; Mast, Natalia; Pikuleva, Irina A (2015) Cholesterol hydroperoxides as substrates for cholesterol-metabolizing cytochrome?P450 enzymes and alternative sources of 25-hydroxycholesterol and other oxysterols. Angew Chem Int Ed Engl 54:11138-42|
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