The research proposal in this application is based on a problem for which the applicant has been the intellectual force: the influence of dietary lipids on the metabolism of xenobiotics. This area is important because health or disease often reflects the balance between reactions that convert non-toxic substances to toxic ones versus reactions that detoxify proximate toxins. Impairment of a major pathway of elimination, such as glucuronidation, could lead to acute disease (drug toxicity) or chronic disease (neoplasia). Treatment with a lipid composition of the microsomal membrane. The specific research to be pursued in the next 5 years pertains to how the lipid content and composition of oral and intravenous diets modulate the function of GT. Aside from demonstrating the effects of diet on the activity of GT in rat microsomes, it will be important to determine how these diet-dependent changes are produced. The extent to which changes in enzyme activity reflect altered amounts of enzyme and/or changes in the functional state of the enzyme will be determined. The effects of dietary lipids on acetaminophen glucuronidation in rats will be measured to show that diet-dependent changes in the functional state/amount of GT have an impact on the rate and pathways of metabolism of a therapeutic agent.
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