We have recently found that within the adrenal cortex there are regional differences in the """"""""activation"""""""" of toxic substances as well as in steroid metabolism. As a result, certain regions of the gland and the functions associated with those regions may be highly vulnerable to the toxic effects of chemical agents. The objectives of the proposed investigations are 1) to evaluate the mechanisms responsible for the functional differences between the different anatomical zones of the adrenal cortex, and 2) to determine the factors affecting and mechanisms involved in the regulation of xenobiotic metabolism and toxicity in each zone. Xenobiotic and steroid metabolism by whole cells and by subcellular fractions from each of the zones of the guinea pig adrenal cortex will be studied with the use of radioimmunoassays, HPLC, mass spectroscopy, and e.s.r. spectroscopy. Secretion of corticosteroids and androgens as well as the metabolism of radiolabelled steroid precursors in each zone will be compared and the effects of exposure to the adrenal toxins, CC14 and CC13, on the morphology and function of each zone determined. The metabolism and/or activation of CC1-4 and CHC1-3, and the relationship between activating and detoxifying pathways in each zone will be evaluated. The role of endogenous antioxidants (ascorbate, Alpha-tocopherol, glutathione, retinol) in modulating the adrenal response to toxins and in the regulation of metabolism will be studied. The effects of antioxidants will be studied in vivo by depletion and repletion experiments, and in vitro by direct addition to adrenal cell preparations. The zonal distribution of antioxidants within the adrenal cortex will be determined and the effects of exposure to adrenal toxins on antioxidant levels in each zone will be studied. The effects of antioxidants on lipid peroxidation in adrenal cells and subcellular fractions and the consequences of lipid peroxidation on cell function in each zone will also be examined. The regulation of xenobiotic and steroid metabolism in each zone will be studied in vivo and with cultured adrenal cells in vitro. Effects of several physiological factors (ACTH, age, sex, steroid hormones) on growth and morphology as well as on xenobiotic activation, antioxidant levels, and lipid peroxidation in each zone will be evaluated. These investigations should contribute to a fuller understanding of the mechanisms involved in the effects of foreign compounds on the adrenal cortex and the role of adrenal antioxidants and other physiological factors in modulating the response of the adrenal to such toxins.
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