The cytotoxic and mutagenic properties of cholesterol oxidation products.

The oxidation of cholesterol proceeds as part of the lipid peroxidation process in membranes. Several oxidation products characteristic of a free-radical mechanism are formed and some can serve as indices of the nature and extent of cholesterol oxidation and of lipid peroxidation in general. Among the most typical oxidation products of lipid peroxide-dependent propagation reactions are the enantiomeric 5,6-epoxides and 7-ketocholestanol. Small amounts of these compounds may persist in tissues experiencing lipid peroxidation at a low but steady flux of free-radical reactions. Supporting evidence includes the routine detection of small quantities of cholesterol epoxides in tissues of normal animals, and the increase of these epoxides under conditions of oxidant stress or antioxidant deficiency. Conversion of cholesterol epoxides to cholestane triol is expected in cells possessing cholesterol epoxide hydrolase. All of these oxidation products possess remarkable cytotoxicity (at least part of which may be due to effects on the cell membrane) causing an increase in intracellular calcium. The cholesterol epoxides are also weakly mutagenic, although the mechanism for this mutagenicity remains to be clarified. In contrast, the other lipid epoxides normally encountered in tissues (chiefly fatty acid epoxides) are not mutagenic, and are much less toxic than the oxysterols described. The cytotoxicity of several oxysterols may be due to a number of mechanisms. That only the epoxides are mutagenic suggests that genotoxicity is a function of their electrophilic reactivity. This is not consistently apparent with the other compounds examined.