title: Implications of cholesterol autoxidation products in the pathogenesis of inflammatory diseases.
abstract: There is rising interest in non-enzymatic cholesterol oxidation because the resulting oxysterols have biological activity and can be used as non-invasive markers of oxidative stress in vivo. The preferential site of oxidation of cholesterol by highly reactive species is at C7 having a relatively weak carbon-hydrogen bond. Cholesterol autoxidation is known to proceed via two distinct pathways, a free radical pathway driven by a chain reaction mechanism (type I autoxidation) and a non-free radical pathway (type II autoxidation). Oxysterols arising from type II autoxidation of cholesterol have no enzymatic correlates, and singlet oxygen ((1)ΔgO2) and ozone (O3) are the non-radical molecules involved in the mechanism. Four primary derivatives are possible in the reaction of cholesterol with singlet oxygen via ene addition and the formation of 5α-, 5β-, 6α- and 6β-hydroxycholesterol preceded by their respective hydroperoxyde intermediates. The reaction of ozone with cholesterol is very fast and gives rise to a complex array of oxysterols. The site of the initial ozone reaction is at the Δ5,6 -double bond and yields 1,2,3-trioxolane, a compound that rapidly decomposes into a series of unstable intermediates and end products. The downstream product 3β-hydroxy-5-oxo-5,6-secocholestan-6-al (sec-A, also called 5,6-secosterol), resulting from cleavage of the B ring, and its aldolization product (sec-B) have been proposed as a specific marker of ozone-associated tissue damage and ozone production in vivo. The relevance of specific ozone-modified cholesterol products is, however, hampered by the fact sec-A and sec-B can also arise from singlet oxygen via Hock cleavage of 5α-hydroperoxycholesterol or via a dioxietane intermediate. Whatever the mechanism may be, sec-A and sec-B have no enzymatic route of production in vivo and are reportedly bioactive, rendering them attractive biomarkers to elucidate oxidative stress-associated pathophysiological pathways and to develop pharmacological agents.
authors.affiliation: Laboratory of Biochemistry, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, Graduate Program in Food and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. Electronic address: miyoshin@u-shizuoka-ken.ac.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Miyoshi
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Laboratory of Vascular Biology and Mass Spectrometry, Sapienza University of Rome, Latina 04100, Italy. Electronic address: luigi.iuliano@uniroma1.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Iuliano
authors.affiliation: Laboratory of Biochemistry, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, Graduate Program in Food and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tomono
authors.affiliation: Laboratory of Biochemistry, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, Graduate Program in Food and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohshima
mesh_terms: D015415:Biomarkers / Q000032:analysis; D002623:Chemistry Techniques, Analytical; D002778:Cholestanones / Q000032:analysis / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005609:Free Radicals; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010126:Ozone / Q000737:chemistry / Q000378:metabolism; D012632:Secosteroids / Q000032:analysis / Q000378:metabolism*; D026082:Singlet Oxygen / Q000737:chemistry / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002778:Cholestanones; D005609:Free Radicals; D012632:Secosteroids; D026082:Singlet Oxygen; D010126:Ozone; C082684:3-hydroxy-5-oxo-5,6-secocholestan-6-al; D002784:Cholesterol
keywords: Cholesterol autoxidation; Inflammation; Oxidative stress; Oxysterols; Secosterol