Hypothesis: Disordered fatty acid metabolism as a result of inborn errors or other pathophysiological conditions (such as diabetes, uremia, etc.) is related to the endogenous production of unsaturated short chain fatty acids. These acids are derived from dehydrogenation of saturated short chain fatty acids and undergo oxidation to an epoxide intermediate. In the normal environment, these epoxides are detoxified by hydration to non-toxic polyhydroxy- carboxylic acids. Whereas, in disorders, as a result of increased production or decreased hydration, the epoxides accumulate and act as inhibitor to enzymes responsible for fatty acid oxidation. Methods: In fasting metabolism and inborn errors of fatty acid metabolism, a number of carboxylic acids, possibly derived from unsaturated short chain carboxylic acids, are found to be significantly elevated. Studies are proposed to elucidate the role of epoxides in the pathogenesis of disordered fatty acid metabolism. The metabolic conversion and fatty acid oxidation inhibition of 2-butenoic, hexa-2,4-dienoic, unsaturated short chain dicarboxylic acids, as well as their epoxides, will be investigated in the rats. Substantial efforts will be devoted to the elucidation of structures of a number of unknown urinary metabolites found in disordered fatty acid metabolism. Model studies using fatty acid oxidation inhibitors, such as hypoglycin, 4-pentenoic acid, valporic acid, and tetradecylglycidic acid, will be compared with data obtained from potential endogenous metabolic toxins (unsaturated short chain fatty acids and their epoxides). Structure-activity relationship of 2,3-substitured oxirane carboxylic acids toward fatty acid oxidation inhibition will be investigated. As a long term goal, we hope to elucidate the toxic mechanisms of different variants of disordered fatty acid metabolism.
