CORTICOSTEROID METABOLISM IN JUVENILE HYPERTENSION

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We are studying a recently discovered form of juvenile hypertension. In this condition the affected children are unable to oxidize cortisol to cortisone. We plan to provide further evidence that children with this condition, which has been named Apparent Mineralocorticoid Excess (AME), and is characterized by hyporeninemia and hypoaldosteronism, have corticosteroid 11Beta-dehydrogenase deficiency as an underlying defect. We also plan to study the metabolism of corticosteroids in a disease in which the underlying biochemical abnormality appears to be the inability to reduce cortisone to cortisol. The existence of these complementary conditions has led us to propose that 11Beta-hydroxysteroid dehydrogenase (11-HSD) which catalyzes the reversible interconversion of 11-oxo and 11-hydroxy groups of corticosteroids is a complex made up of separate, yet interdependent 11Beta-dehydrogenase and 11-reductase components. Information from the literature on the properties of 11-HSD is consistent with a multi-enzyme structure. We will purify enzyme from chicken or duck liver, which contains 11-reductase with no detectable 11-dehydrogenase, and from monkey placenta, which contains 11-dehydrogenase and no detectable 11-reductase. We will isolate 11-HSD which contains both activities from adult rat liver and attempt to separate the oxidase and reductase components. The dehydrogenases will be purified by a combination of high performance chromatographic techniques and affinity precipitation with bifunctional ligands. Stabilization of the readily inactivated 11-reductase by glycerol or other agents will be attempted preliminary to its purification. Separation of 11-dehydrogenase and 11-reductase will be achieved by chromatographic and electrophoretic methods. The 11-reductase will be purified by procedures similar to those used for 11-dehydrogenase purification. The kinetic and physico-chemical properties of the enzymes will be studied in detail, in order to define the effects of the environment on their behavior and to determine their multiplicity. These investigations will contribute (a) to an understanding of how oxidation and reduction of corticosteroids at C-11 are controlled during metabolism; and (b) to insight into the origin of disturbances in 11-HSD in human disease.