Adenyl cyclase in human hair follicles: Its inhibition by dihydrotestosterone

doi:10.1016/0006-291X(70)90166-X

Biochemical and Biophysical Research Communications

Volume 41, Issue 4, 25 November 1970, Pages 884-890

https://doi.org/10.1016/0006-291X(70)90166-X Get rights and content

Abstract

Particulate fractions obtained from human scalp hair follicles contained adenyl cyclase activity which was activated by estrone and inhibited by dihydrotestosterone (5α-androstan-17β-ol-3-one)^∗. The marked inhibition of this enzyme activity by dihydrotestosterone but not by testosterone suggests that the former is the tissue-active androgen. We then speculate that the initial step in the development of pattern baldness is controlled by the intracellular level of dihydrotestosterone rather than testosterone as mediated by adenyl cyclase (and cyclic AMP).

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The conversion of testosterone (T) to dihydrotestosterone (DHT) has been demonstrated to be catalysed by at least two isoforms of human steroid 5α-reductase, designated types I and II. Type II 5α-reductase expression predominates in human accessory sex tissues, localized to the fibromuscular stromal compartment. The type I isoform predominates in skin, prostatic epithelia and, to a lesser extent, in prostatic fibromuscular stroma. The significance of the type I isoform to prostatic cellular growth and function remains undefined. In cultured DU145 cells, we evaluated the metabolism of [¹⁴C]-T and demonstrated the time-dependent formation of [¹⁴C]-DHT. Oxidative metabolism (conversion of [¹⁴C]-T to [¹⁴C]-androstenedione) and the formation of conjugated androgen metabolites occurred at a relatively low rate in the DU145 cells. Using human type I 5α-reductase cDNA, Northern blot analysis of DU145 cell mRNA revealed high levels of type I isoform expression. Analogous probing of the DU145 cells with a human 5α-reductase II cDNA failed to reveal expression of the type II isoform. The expression of functional type I activity has been confirmed pharmacologically using isoformselective 5α-reductase inhibitors. Reductive metabolism of [³H]-T in the DU145 cells was inhibited in a concentration-dependent manner by LY306089, a potent non-steroidal type I-selective inhibitor (IC₅₀ = 10.0 nM). SKF105657, a steroidal type II-specific inhibitor was distinctly less active at inhibiting [³H]-DHT formation. LY306089 was a non-competitive inhibitor of type I 5α-reductase in DU145 cellular homogenates with an apparent K_i value of 4.0 nM. These studies have identified and pharmacologically defined type I 5α-reductase activity in an androgen-insensitive prostatic cancer cell line and provide the basis for additional investigations into the significance of type I 5α-reductase to human prostatic pathophysiology.
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A hereditary, androgen-driven disorder, androgenetic alopecia is the most common form of alopecia in humans: its prevalence is 23–87%. Central alopecia is more severe in men; women are more likely to experience diffuse thinning. The acute onset of alopecia in those with inflammatory diseases of the scalp suggests a variety of etiologies, including the impact of inflammatory cells, release of cytokines, presence of growth factors, and increased interaction of stromal cells. Therapeutic modalities, which are most effective when used in combinations, utilize hair growth promoters, antiandrogens, and androgen blockade agents.
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Our current knowledge of androgenetic alopecia and hair follicle metabolism and control has evolved from four phases of scientific evolution. In the first phase, which I have called the era of science, investigators made strides in understanding androgen metabolism in general and clarified the role of androgens in androgenetic alopecia in particular. This phase was followed by what I have labeled the era of antiandrogens when they were sought as the ideal and only treatment for androgenetic alopecia. Though valid, this approach has proved to be limited. The third phase of scientific progress, the era of biologic response modifiers, evolved when investigators discovered a group of unrelated drugs that promoted hair growth. These drugs have a variety of physiologic effects and may act synergistically to stimulate hair follicle growth. Finally, we are on the threshold of the fourth phase, the era of predictability, in which research efforts will focus on finding the active hair growth-promoting sites on these drug molecules, and on clarifying how these drugs, such as minoxidil, stimulate hair growth on physiologic, pharmacologic, biochemical, and molecular levels.
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^∗: The following trivial names are used in this text: dihydrotestosterone = 5α-androstan-17β-ol-3-one; androstenedione = 4-androstene-3, 17-dione; DHA = dehydroepiandrosterone = 5 - androsten-3β-ol-17-one; estrone = 1, 3, 5 (10)-estratrien-3-ol-17-one; estradiol - 17β = 1, 3, 5 (10)-estratrien-3, 17β-diol; progesterone = 4 - pregnen-3, 20-dione; and pregnenolone = 5 - pregnen-3β-ol-20-one.

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Adenyl cyclase in human hair follicles: Its inhibition by dihydrotestosterone

Abstract

J. Invest. Derm

J. Biol. Chem

J. Biol. Chem

J. Biol. Chem