Our interdisciplinary team plans to define how and to what extent drugs affect vitamin A status. One main target will be drug induced alterations of retinol metabolism. We will study two microsomal systema recently discoverd by us, one of which requires NAD but is distinct from the cytosolic retinol dehydrogenase pathway; it will be assessed, in part, in a deermouse strain which we found to lack cytosolic retinol dehydrogenase. The other system involves cytochrome P-450. We will evaluate the effect of chronic drug administration on the activity of this microsomal pathway; Antibodies against the various forms of P-450 which are now available to us will allow the assessment of the respective contribution of each isozyme to the microsomal metabolism of reginol and/or retinoic acid. Furthermore, using reconstituted systems, we will determine the specificity of these isozymes, to what degree other substrates for these systems, such as drugs and carcinogens, interact with this process and, vice versa, to what extent vitamin A interferes with the activation of carcinogens. We also will evaluate hepatic vitamin A depletion after drug administration and asess putative mechanisms, including increased catabolism, biliary excretion as well as mobilization from the liver to other tissues. We will explore possible sequelae of hepatic retinol depletion in terms of ultrastructural and functional damage to the Golgi complex, lysosomes and plasma membranes, changes in glycoproteins and impairment of lipoprotein secretion. Damage to mucosal epithela, particularly its relationship to precancerous lesions, will be assessed. Finally, we will define the optimal dose of vitamin A supplementation needed to correct lesions related to vitamin A depletion and how drug administation affcts vitamin A toxicity. Parameters of toxicity will include lipid accumulation, membrane alterations, ultrastructural and functional abnormalities of mitochondria and enhanced fibrosis. Hepatic collagen mRNA and its transcriptional control will be evaluated with a cDNA probe and in situ hybridization. Activation of Ito cells and myofibroblasts will be assessed in tissues and cell cultures. In addition, a pilot clinical study on vitamin A-drug interactions will be conducted. Our ultimate goals are 1) to gather information needed to recognize conditions that result in vitamin A depletion in association with the use and abuse of drugs and food additives 2) to determine to what extent liver damage may ensue and 3) to define the """"""""therapeutic window"""""""" that pertains to vitamin A supplementation.
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