Insulin-dependent diabetes mellitus, irregardless of its etiology, is a hormonal disorder related primarily to the lack of or a deficiency of insulin. A consequence of diabetes is altered hepatic metabolism of drugs. This consequence of diabetes is of considerable pharmacological importance since it can affect the efficacy and toxicity of drugs. Equally as important, the alteration of this fundamental oxidative process by diabetes can affect the susceptibility of diabetics to chemical toxicants and carcinogens encountered in the environment. The applicant has isolated from rat liver a unique, diabetes-dependent xenobiotic metabolizing enzyme. The catalytic and other properties of this enzyme indicate that it is a terminal entity responsible for substrate specific alterations in xenobiotic metabolism observed in diabetic rats. The results of preliminary studies suggest that insulin and corticosteroids have a """"""""repressor"""""""" and an """"""""inducer"""""""" function, respectively, in regulating the appearance of this unique enzyme. It is proposed to further characterize this unique diabetes-dependent enzyme (amino acid composition and sequence analysis and carbohydrate content analysis) and to use monospecific antibodies to the enzyme to study the biochemical events, especially hormonal, associated with its synthesis (appearance) and degradation (disappearance) in vivo. Also, in order to understand the mechanisms that direct the appearance of the enzyme, specific mRNA directed synthesis of this unique enzyme or its precursor and subsequent post-translational modification will be examined in vitro.
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