Cytotoxic Mechansims for Cholesterol Oxidation Products in Fibroblasts and Endothelial Cells

摘要: Several cholesterol oxides form during free radical oxidation of membrane lipids. These have been recovered from tissues and at least eight these are products consistently detected after oxy-radical induced The proportions can serve as a “fingerprint” the process in membranes. Three common tested for their cytotoxic potency cell culture systems. isomeric 5,6 epoxides, 7-keto-cholesterol cholestane-3β,5α,6β-triol potent cytotoxins with remarkable stability under conditionsof culture. All three compounds toxic concentrations half that seen bile acids such lithocholic, cholic or deoxycholic acids. Their toxicity appears to be directed towards includes marked perturbations calcium homeostasis. each compound follows order: pulmonary endothelial cells > lung fibroblasts (V79 cells) hepatocytes. oxide is reduced more than 50% deficient media (<0.05 mM) indicating involvement cytotoxicity. LD50 cholestane triol (20 uM) approaches linoleic acid hydroperoxides (10 cells. Although represent most sensitive type examined virtually all oxides, displays approximately equal sensitivity hydroperoxides. In addition toxicity, epoxides also produce DNA damage which correlates extensive binding. weak mutagens demonstrated V79 A unique aspect epoxide LD50’s IC50’s.(ie. inhibition synthesis) both cells, suggesting two events may proceed via mechanism. Since major derived lipid peroxidation, rapidly accumulation on treatment membranous other organic hydroperoxides, it concievable number effects peroxides attributable long-lived produced.