Free radical oxidation of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders.
Free radical oxidation of cholesterol and its precursors contribute significantly to the pathophysiology of a number of human diseases. This review intends to summarize recent developments and provide a perspective on the reactivities of sterols toward free radical oxidation, the free radical reaction mechanism, and the biological consequences of oxysterols derived from the highly oxidizable cholesterol precursor, 7-dehydrocholesterol. We propose that the rigid structures, additional substituents on the double bonds, and the well-aligned reactive C-H bonds in sterols make them more prone to free radical oxidation than their acyclic analogs found in unsaturated fatty acids. The mechanism of sterol peroxidation follows some well-established reaction pathways found in the free radical peroxidation of polyunsaturated fatty acids, but sterols also undergo some reactions that are unique to these compounds. Peroxidation of 7-dehydrocholesterol gives arguably the most diverse set of oxysterol products that have been observed to date. The metabolism of these oxysterols in cells and the biological consequences of their formation will be discussed in the context of the pathophysiology of the human disease Smith-Lemli-Opitz syndrome. Considering the high reactivity of sterols, we propose that a number of other cholesterol biosynthesis disorders may be associated with oxidative stress.
Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, TN , USA.
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D002784:Cholesterol / Q000096:biosynthesis*; D005609:Free Radicals / Q000737:chemistry; D006801:Humans; D010084:Oxidation-Reduction; D019082:Smith-Lemli-Opitz Syndrome / Q000209:etiology / Q000378:metabolism*; D013261:Sterols / Q000737:chemistry* / Q000378:metabolism
D005609:Free Radicals; D013261:Sterols; D002784:Cholesterol
7-dehydrocholesterol; Smith–Lemli–Opitz syndrome; autoxidation; oxysterol; peroxidation