title: Cholesterol hydroperoxides as substrates for cholesterol-metabolizing cytochrome P450 enzymes and alternative sources of 25-hydroxycholesterol and other oxysterols.
abstract: The interaction of the primary autoxidation products of cholesterol, namely 25- and 20ξ-hydroperoxides, with the four principal cholesterol-metabolizing cytochrome P450 enzymes is reported. Addition of cholesterol 25-hydroperoxide to the enzymes CYP27A1 and CYP11A1 induced well-defined spectral changes while generating 25-hydroxycholesterol as the major product. The 20ξ-hydroperoxides induced spectral shifts in CYP27A1 and CYP11A1 but glycol metabolites were detected only with CYP11A1. CYP7A1 and CYP46A1 failed to give metabolites with any of the hydroperoxides. A P450 hydroperoxide-shunt reaction is proposed, where the hydroperoxides serve as both donor for reduced oxygen and substrate. CYP27A1 was shown to mediate the reduction of cholesterol 25-hydroperoxide to 25-hydroxycholesterol, a role of potential significance for cholesterol-rich tissues with high oxidative stress. CYP27A1 may participate in the removal of harmful autoxidation products in these tissues, while providing a complementary source of 25-hydroxycholesterol, a modulator of immune cell function and mediator of viral cell entry.
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4 (Canada). Johan.E.vanlier@USherbrooke.ca.
authors.forename: Johan E
authors.initials: JE
authors.lastname: van Lier
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106 (USA)[*]Corresponding authors.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mast
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106 (USA)[*]Corresponding authors. iap8@case.edu.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Pikuleva
mesh_terms: D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006888:Hydroxycholesterols / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D006888:Hydroxycholesterols; D013261:Sterols; C007997:25-hydroxycholesterol; C002843:cholesterol hydroperoxide; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol
keywords: autooxidation; biocatalysis; cholesterol hydroperoxides; cytochrome p450; metabolism