The transformation of androgens to estrogens involves three hydroxylations, the first two of which take place at the C-19 position and third at 2Beta. The product of these reactions the 2Beta-hydroxy-19-aldehyde, is transformed nonenzymatically to estrogen. An antibody to the 2Beta-hydroxy aldehyde has been prepared and it inhibits estrogen formation by delaying the collapse of the labile enzymatic product of placental aromatase. The purpose of this project is to utilize this immunological probe and the high specific activity androgen substrates which have been synthesized, to examine the individual hydroxylations participating in estrogen biosynthesis in tissues other than the placenta such as the gonads, brain and adipose tissue. The step(s) in the aromatization sequence which are influenced by pituitary hormones will be analyzed by means of the above probes. The new radiolabeled substrates will be employed to examine changes in peripheral aromatization in in vivo studies contrasting normals and subjects with body weight distortions, as well as patients with liver disease. The mechanism of estrogen biosynthesis will provide the basis for the synthesis of structures which bid well to be effective and specific aromatization inhibitors and can prove to be useful therapeutic agents in diseases in which cessation of estrogen biosynthesis is desirable.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD018350-03
Application #
3315387
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1984-02-01
Project End
1987-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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Norton, B I; Miyairi, S; Fishman, J (1988) 19-Hydroxylation of androgens by rat granulosa cells. Endocrinology 122:1047-52
Fishman, J; Hahn, E F (1987) The nature of the final oxidative step in the aromatization sequence. Steroids 50:339-45
Michnovicz, J J; Hahn, E F; Fishman, J (1987) 19-Hydroxylation and aromatization of androgens in the developing rat brain. Endocrinology 121:1209-14
Stone, N N; Fair, W R; Fishman, J (1986) Estrogen formation in human prostatic tissue from patients with and without benign prostatic hyperplasia. Prostate 9:311-8
Miyairi, S; Fishman, J (1986) 3-Methylene-substituted androgens as novel aromatization inhibitors. Evidence of a requirement for C-3 oxygen in C-19 hydroxylations. J Biol Chem 261:6772-7
Hahn, E F; Fishman, J (1985) Stereochemistry of 1,2-hydrogen loss during aromatization in the brain. J Steroid Biochem 22:597-600
Hahn, E F; Miyairi, S; Fishman, J (1985) 19-Hydroxylation of androgens in the rat brain. Proc Natl Acad Sci U S A 82:2728-30