KINETICS OF RETINOID METABOLISM BY ALCOHOL DEHYDROGENASE

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Retinol (vitamin A), produced in the gastrointestinal tract after ingestion of beta-carotene, is oxidized to retinal in the liver. Retinal is important for night vision, and retinoid acid, and product of retinal, is important in cell development. Retinol, retinal, and retinoid acid are among a class of retinoids, and retinoid levels are correlated with fetal alcohol syndrome and night blindness, effects associated with alcoholism. It has been hypothesized that human cytosolic alcohol dehydrogenase isoenzymes in the stomach and liver function as physiological enzymes in retinoid metabolism, and that ingested ethanol interferes with this process. The purpose of this two- year exploratory proposal is to determine the feasibility of using steady-state, stopped-flow, and rapid scanning kinetics, and computer simulation to test this hypothesis. A set of kinetic data will be collected that describes the individual steps of all-trans-retinoid and 11-cis-retinoid metabolism by liver and gastric alcohol dehydrogenase isoenzymes at 37 degrees Celsius. In the cell, retinoids are transported by a class of binding proteins called cellular retinoid binding proteins (CRBP). The role of CRBP, as well as of ethanol and acetaldehyde, in retinoid metabolism by the alcohol dehydrogenase isozymes will also be evaluated. These kinetics data will be used to perform a series of computer-based simulation experiments that investigate the effect of enzyme, substrate, and product of retinoid metabolism. These experiments will contribute to efforts in identifying the role of human cytosolic alcohol dehydrogenase isoenzymes in retinoid metabolism in the liver and gastrointestinal tract, and will evaluate the role of ethanol in the perturbation of retinoid metabolism by these enzymes.