title: The effect of oxidizing cholesterol on gastrointestinal absorption, plasma clearance, tissue distribution, and processing by endothelial cells.
abstract: Little is known about the absorption or metabolism of oxysterols. Toward better appreciating the metabolic consequences of oxidizing cholesterol, we compared labeled cholesterol with the labeled oxysterols 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, and 7-ketocholesterol prepared from [4-14C]cholesterol, [26,26,26,27,27,27-2H6]cholesterol, and [23,24,25,26,27-13C5] cholesterol. Gastrointestinal absorption of oxysterols in rats was 91.5 +/- 0.3% compared with 75 +/- 1.1% for cholesterol, determined by fecal collection (P < .001). When injected intravenously and followed by gas chromatography/mass spectrometry, 7 alpha-hydroxycholesterol was cleared at 23 times the rate of cholesterol. After 5 minutes, only 1.2 +/- 0.2% of 7 alpha-hydroxycholesterol remained in the plasma, whereas 28.0 +/- 1.7% of cholesterol and 40.0 +/- 2.5% of a triglyceride emulsion injected simultaneously were still present. [14C]7 alpha-Hydroxycholesterol injected intravenously was also rapidly cleared from plasma, was widely distributed in tissues and organs, and showed evidence of extensive metabolism at 5 minutes. The fractional rate of uptake of radiolabeled oxysterols by cultured endothelial cells was 15.7 times that of cholesterol (P < .001), and the fractional rate of efflux was 3.4 times that of cholesterol (P < .001). Oxysterols passed through endothelial cells grown on transwell membranes at a rate 4.3 times that of cholesterol (P < .001). Fractional oxysterol transport across the endothelial cell monolayer was increased 62 +/- 17% when HDL was added to the medium in the lower chamber (P = .003). Oxysterols were extensively metabolized to even more polar metabolites during endothelial cell transit. These properties of oxysterols potentially provide a mechanism for enhancing transport of cholesterol through tissues and preventing accumulation of cholesterol in those cells that can oxidize it.
authors.affiliation: Metabolism Division, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Krut
authors.forename: J W
authors.initials: JW
authors.lastname: Yang
authors.forename: G
authors.initials: G
authors.lastname: Schonfeld
authors.forename: R E
authors.initials: RE
authors.lastname: Ostlund
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D006888:Hydroxycholesterols / Q000378:metabolism*; D007408:Intestinal Absorption; D007653:Ketocholesterols / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010084:Oxidation-Reduction; D051381:Rats; D014018:Tissue Distribution
chemical_list: D006888:Hydroxycholesterols; D007653:Ketocholesterols; C011724:cholest-5-en-3 beta,7 alpha-diol; D002784:Cholesterol; C003001:7-ketocholesterol