Several mechanisms have been described for the cytotoxic effects of free radicals. The radical species of oxygen, and subsequent reaction products arising from oxygen radical interactions have been shown to cause cell damage and may also be mutagenic and carcinogenic. Perhaps the most vulnerable of the cell components to free radical damage are the unsaturated lipids. Free radical initiation of lipid peroxidation yields numerous oxidation products which are disruptive to membrane structure and cytotoxic. Lipid hydroperoxides have long been known for their toxic effects, but there is a growing body of evidence demonstrating that secondary or decomposition products possess significant biological activities, and toxic properties. One representative class of lipid peroxidation products isolable from biological systems consists of lipid expoxides. Lipid epoxides belong to a broad range of electrophilic compounds and as such have the potential to alkylate cell components. A commonly encountered product, cholesterol epoxide, has been shown to be mutagenic and carcenogenic in a number of diverse studies. We have gathered evidence to show that the mutagenic properties of this epoxide, and possibly other lipid epoxides, is influenced by metabolism. This process depends to a considerable extent on epoxide hydrolase. A systematic investigation of lipid epoxide formation in model membranes subjected to radical generating systems, delination of peroxidizing conditions which favor epoxide formation, characterization of major epoxide products and measurement of their reactivity will serve as a basis and criteria for examining cytotoxicity and genotoxicity in mammalian cells. These observations combined with measurements of the rates of their metabolism will be the basis for predicting genetoxicity which can then be tested using V79 Chinese hamster lung fibroblasts. V79 cells will be used to measure the uptake, metabolism, cytotoxicity and mutagenesis of lipid epoxides. Further experiments will be conducted to elaborate on initial findings that expression of genotoxicity following treatments with lipid epoxides can be influenced through metabolism. These studies are unique in that they consider the genesis and metabolic fate of potential carcinogens which are found entirely in vivo.
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