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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037094-02
Application #
3235799
Study Section
Endocrinology Study Section (END)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Population Council
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10017
Agarwal, A K; Mune, T; Monder, C et al. (1995) Mutations in putative glycosylation sites of rat 11 beta-hydroxysteroid dehydrogenase affect enzymatic activity. Biochim Biophys Acta 1248:70-4
White, P C; Mune, T; Agarwal, A K (1995) Functional studies of 11 beta-hydroxysteroid dehydrogenase. Steroids 60:65-8
Agarwal, A K; Mune, T; Monder, C et al. (1995) Cloning of cDNA encoding an NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase in sheep kidney. Endocr Res 21:389-97
Monder, C; Miroff, Y; Marandici, A et al. (1994) 11 beta-Hydroxysteroid dehydrogenase alleviates glucocorticoid-mediated inhibition of steroidogenesis in rat Leydig cells. Endocrinology 134:1199-204
Monder, C; Sakai, R R; Miroff, Y et al. (1994) Reciprocal changes in plasma corticosterone and testosterone in stressed male rats maintained in a visible burrow system: evidence for a mediating role of testicular 11 beta-hydroxysteroid dehydrogenase. Endocrinology 134:1193-8
White, P C; Obeid, J; Agarwal, A K et al. (1994) Genetic analysis of 11 beta-hydroxysteroid dehydrogenase. Steroids 59:111-5
Ten Cate, W J; Monder, C; Marandici, A et al. (1994) 11 beta-Hydroxysteroid dehydrogenase in the rat inner ear. Am J Physiol 266:E269-73
Agarwal, A K; Mune, T; Monder, C et al. (1994) NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase. Cloning and characterization of cDNA from sheep kidney. J Biol Chem 269:25959-62
White, P C (1994) Disorders of aldosterone biosynthesis and action. N Engl J Med 331:250-8
Monder, C; White, P C (1993) 11 beta-hydroxysteroid dehydrogenase. Vitam Horm 47:187-271

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