Non-stereo-selective cytosolic human brain tissue 3-ketosteroid reductase is refractory to inhibition by AKR1C inhibitors |
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Authors: | Stephan Steckelbroeck Dieter Lütjohann David R Bauman Michael Ludwig Anke Friedl Volkmar HJ Hans Trevor M Penning Dietrich Klingmüller |
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Institution: | 1. Institute of Clinical Chemistry and Pharmacology, University of Bonn, 53105 Bonn, Germany;2. Paul-Ehrlich-Institut, 63225 Langen, Germany;3. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA;4. Institute of Neuropathology, University of Bonn, 53105 Bonn, Germany;5. Institute of Neuropathology, Evangelisches Krankenhaus Bielefeld, 33617 Bielefeld, Germany |
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Abstract: | Cerebral 3α-hydroxysteroid dehydrogenase (3α-HSD) activity was suggested to be responsible for the local directed formation of neuroactive 5α,3α-tetrahydrosteroids (5α,3α-THSs) from 5α-dihydrosteroids. We show for the first time that within human brain tissue 5α-dihydroprogesterone and 5α-dihydrotestosterone are converted via non-stereo-selective 3-ketosteroid reductase activity to produce the respective 5α,3α-THSs and 5α,3β-THSs. Apart from this, we prove that within the human temporal lobe and limbic system cytochrome P450c17 and 3β-HSD/Δ5–4 ketosteroid isomerase are not expressed. Thus, it appears that these brain regions are unable to conduct de novo biosynthesis of Δ4-3-ketosteroids from Δ5-3β-hydroxysteroids. Consequently, the local formation of THSs will depend on the uptake of circulating Δ4-3-ketosteroids such as progesterone and testosterone. 3α- and 3β-HSD activity were (i) equally enriched in the cytosol, (ii) showed equal distribution between cerebral neocortex and subcortical white matter without sex- or age-dependency, (iii) demonstrated a strong and significant positive correlation when comparing 46 different specimens and (iv) exhibited similar sensitivities to different inhibitors of enzyme activity. These findings led to the assumption that cerebral 3-ketosteroid reductase activity might be catalyzed by a single enzyme and is possibly attributed to the expression of a soluble AKR1C aldo-keto reductase. AKR1Cs are known to act as non-stereo-selective 3-ketosteroid reductases; low AKR1C mRNA expression was detected. However, the cerebral 3-ketosteroid reductase was clearly refractory to inhibition by AKR1C inhibitors indicating the expression of a currently unidentified enzyme. Its lack of stereo-selectivity is of physiological significance, since only 5α,3α-THSs enhance the effect of GABA on the GABAA receptor, whereas 5α,3β-THSs are antagonists. |
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Keywords: | Δ4-androstenedione Androst-4-ene-3 17-dione 5α-androstanedione 5α-androstane-3 17-dione epi/androsterone 3β/3α-hydroxy-5α-androstane-17-one testosterone 17β-hydroxyandrost-4-ene-3-one 5α-dihydrotestosterone [5α-DHT] 17β-hydroxy-5α-androstane-3-one 3β/3α-androstanediol 5α-androstane-3β/3α 17β-diol dehydroepiandrosterone [DHEA] 3β-hydroxyandrost-5-ene-17-one Δ5-androstenediol androst-5-ene-3β 17β-diol progesterone preg-4-ene-3 20-dione 5α-dihydroprogesterone [5α-DHP] also known as allopregnanedione 5α-pregnane-3 20-dione 5α 3β/3α-tetrahydroprogesterone [5α 3β/3α-THP] also known as epi/allopregnanolone 3β/3α-hydroxy-5α-pregnane-20-one 5α 20α-tetrahydroprogesterone [5α 20α-THP] 20α-hydroxy-5α-pregnane-3-one pregnenolone 3β-hydroxypreg-5-ene-20-one 17α-hydroxyprogesterone [17α-OHP] 17α-hydroxypreg-4-ene-3 20-dione 20α-hydroxyprogesterone 20α-hydroxypreg-4-ene-3-one 11-deoxycorticosterone [DOC] 21-hydroxypreg-4-ene-3 20-dione pregnenolone 3β-hydroxypregn-5-ene-20-one AKR aldo-keto reductase CX cerebral neocortex DHS dihydrosteroid GAPDH glyceraldehyde-3-phosphate dehydrogenase HSD hydroxysteroid dehydrogenase KSI ketosteroid isomerase SC subcortical white matter THS tetrahydrosteroid |
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