The influence of 4-hydroxy-4-androstene-3,17-dione on androgen metabolism and action in cultured human foreskin fibroblasts

Hsiang Ying-Hui H., Gary Berkovitz, Terry R. Brown, Claude J. Migeon, Angela M H Brodie

Research output: Contribution to journalArticle

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Abstract

4-hydroxy-4-androstene-3,17-dione (4-OHA) has been shown to be a potent inhibitor of aromatase activity. It is effective in the control of estrogen-dependent processes in female subjects and may potentially be useful in the treatment of estrogen-dependent processes in men. Human foreskin fibroblasts grown in cell culture provide a model to investigate the effects of 4-OHA on extraglandular aromatase activity as well as the ability of the compound to influence androgen receptor binding and the 5α-reduction of testosterone (T). Initial experiments were carried out to determine the potency of 4-OHA in genital skin fibroblasts by incubating cells with 4-OHA over a range of concentrations. When aromatase activity was determined at a substrate concentration close to the apparent Km of the enzyme, a 44% inhibition of enzyme activity occurred at a mean concentration of 5 nM 4-OHA. Enzyme kinetic studies analyzed by Eadie-Hofstee plots demonstrated competitive inhibition by 4-OHA with a mean apparent Ki of 2.7 nM. When 5α-reductase activity was determined in the presence of 200 nM [3H]T, in the absence or presence of 4-OHA, a 50% inhibition of enzyme activity occurred at an inhibitor concentration of 3 μM. In androgen receptor binding studies, 4-OHA possessed 1% of the affinity of dihydrotestosterone (DHT) for [3H]DHT binding sites. In summary: 4-OHA is a potent and specific inhibitor of aromatase activity in human genital skin fibroblasts, the affinity of the enzyme for 4-OHA being greater than its affinity for the substrate, adrenostenedione. The influence of 4-OHA on 5α-reductase activity and androgen receptor binding is minimal.

Original languageEnglish
Pages (from-to)131-135
Number of pages5
JournalJournal of Steroid Biochemistry
Volume26
Issue number1
DOIs
StatePublished - Jan 1 1987
Externally publishedYes

Fingerprint

Foreskin
Fibroblasts
Metabolism
Androgens
Androgen Receptors
Enzyme inhibition
Enzymes
Aromatase Inhibitors
Aromatase
Dihydrotestosterone
Enzyme activity
formestane
Skin
Oxidoreductases
Estrogens
Enzyme kinetics
Substrates
Cell culture
Human Activities
Testosterone

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

The influence of 4-hydroxy-4-androstene-3,17-dione on androgen metabolism and action in cultured human foreskin fibroblasts. / Ying-Hui H., Hsiang; Berkovitz, Gary; Brown, Terry R.; Migeon, Claude J.; Brodie, Angela M H.

In: Journal of Steroid Biochemistry, Vol. 26, No. 1, 01.01.1987, p. 131-135.

Research output: Contribution to journalArticle

Ying-Hui H., Hsiang ; Berkovitz, Gary ; Brown, Terry R. ; Migeon, Claude J. ; Brodie, Angela M H. / The influence of 4-hydroxy-4-androstene-3,17-dione on androgen metabolism and action in cultured human foreskin fibroblasts. In: Journal of Steroid Biochemistry. 1987 ; Vol. 26, No. 1. pp. 131-135.
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abstract = "4-hydroxy-4-androstene-3,17-dione (4-OHA) has been shown to be a potent inhibitor of aromatase activity. It is effective in the control of estrogen-dependent processes in female subjects and may potentially be useful in the treatment of estrogen-dependent processes in men. Human foreskin fibroblasts grown in cell culture provide a model to investigate the effects of 4-OHA on extraglandular aromatase activity as well as the ability of the compound to influence androgen receptor binding and the 5α-reduction of testosterone (T). Initial experiments were carried out to determine the potency of 4-OHA in genital skin fibroblasts by incubating cells with 4-OHA over a range of concentrations. When aromatase activity was determined at a substrate concentration close to the apparent Km of the enzyme, a 44{\%} inhibition of enzyme activity occurred at a mean concentration of 5 nM 4-OHA. Enzyme kinetic studies analyzed by Eadie-Hofstee plots demonstrated competitive inhibition by 4-OHA with a mean apparent Ki of 2.7 nM. When 5α-reductase activity was determined in the presence of 200 nM [3H]T, in the absence or presence of 4-OHA, a 50{\%} inhibition of enzyme activity occurred at an inhibitor concentration of 3 μM. In androgen receptor binding studies, 4-OHA possessed 1{\%} of the affinity of dihydrotestosterone (DHT) for [3H]DHT binding sites. In summary: 4-OHA is a potent and specific inhibitor of aromatase activity in human genital skin fibroblasts, the affinity of the enzyme for 4-OHA being greater than its affinity for the substrate, adrenostenedione. The influence of 4-OHA on 5α-reductase activity and androgen receptor binding is minimal.",
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