The adrenal cortex contains very high concentrations of alpha-tocopherol (alpha-T) but little is known about the mechanisms responsible for this localization. Regional differences in the concentrations of alpha-T within the adrenal impact upon lipid peroxidation and steroid metabolism in the different zones of the gland. Recent studies indicate that adrenal content of alpha-T is increased by adrenocorticotropic hormone (ACTH) concomitant with a decline in membrane lipid peroxidation. In addition, adrenal alpha- T concentrations decrease markedly with aging in guinea pigs, accompanied by a decline in adrenal androgen secretion. The immediate objectives of the proposed research are: 1) To determine the mechanisms involved in the regulation of adrenocortical content and disposition of alpha-T, and 2) To determine the mechanism(s) responsible for the decline in adrenal alpha-T content with aging. Guinea pigs will be used for the proposed experiments. Adrenal antioxidant content in vivo will be modulated by dietary manipulation of alpha-T. In vitro studies will be done with intact cells and subcellular fractions from the zona fasciculata (ZF), the adrenal zone having the highest alpha- T content. All studies will be done with cells from young and old animals to determine the basis for the age-related decline in adrenal alpha-T. The subcellular distribution and specific binding sites for alpha-T in ZF cells will be investigated. Mechanisms responsible for the actions of ACTH on the disposition of adrenal alpha-T will be pursued by evaluating its effects on the influx, subcellular distribution, cytosolic binding, metabolism, and efflux of alpha-T in ZF cells. The role of lipoproteins, especially LDL, in the adrenal uptake of alpha-T and in the actions of ACTH on adrenal alpha-T content will be investigated in cultured ZF cells. In addition, studies will be done to determine if the actions of ACTH on adrenal lipid peroxidation are mediated by alpha-T and, consequently, decrease as result of aging. Finally we will determine if dietary alpha-T supplementation in older animals increases adrenal alpha-T levels and increases androgen secretion. These investigations should contribute to a fuller understanding of the regulation of alpha-T in the adrenal cortex and the effects of aging on the regulatory processes.
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