Non-stereo-selective cytosolic human brain tissue 3-ketosteroid reductase is refractory to inhibition by AKR1C inhibitors.
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/Δ(5-4) ketosteroid isomerase are not expressed. Thus, it appears that these brain regions are unable to conduct de novo biosynthesis of Δ(4)-3-ketosteroids from Δ(5)-3β-hydroxysteroids. Consequently, the local formation of THSs will depend on the uptake of circulating Δ(4)-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 GABA(A) receptor, whereas 5α,3β-THSs are antagonists.
Steckelbroeck
Stephan
S
Institute of Clinical Chemistry and Pharmacology, University of Bonn, 53105 Bonn, Germany. st_steckelbroeck@hotmail.com
Lütjohann
Dieter
D
Bauman
David R
DR
Ludwig
Michael
M
Friedl
Anke
A
Hans
Volkmar H J
VH
Penning
Trevor M
TM
Klingmüller
Dietrich
D
D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002855:Chromatography, Thin Layer / Q000379:methods; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007223:Infant; D008875:Middle Aged; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013256:Steroids / Q000737:chemistry; D013702:Temporal Lobe / Q000473:pathology
D013256:Steroids; D015096:3-Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C031298:3-ketosteroid reductase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase