期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1801, 期 11, 页码 1221-1231出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2010.07.005
关键词
Human brain; 3alpha/3beta-hydroxysteroid dehydrogenase; HSD; Aldo-keto reductase; Stereo-selective; GABA-A receptor
资金
- Deutsche Forschungsgemeinschaft [Kl 524/5-1, Kl 524/5-2]
- National Institutes of Health [DK47015, CA90744]
Cerebral 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity was suggested to be responsible for the local directed formation of neuroactive 5 alpha,3 alpha-tetrahydrosteroids (5 alpha,3 alpha-THSs) from 5 alpha-dihydrosteroids. We show for the first time that within human brain tissue 5 alpha-dihydroprogesterone and 5 alpha-dihydrotestosterone are converted via non-stereo-selective 3-ketosteroid reductase activity to produce the respective 5 alpha,3 alpha-THSs and 5 alpha,3 beta-THSs. Apart from this, we prove that within the human temporal lobe and limbic system cytochrome P450c17 and 3 beta-HSD/Delta(5-4) ketosteroid isomerase are not expressed. Thus, it appears that these brain regions are unable to conduct de novo biosynthesis of Delta(4)-3-ketosteroids from Delta(5)-3 beta-hydroxysteroids. Consequently, the local formation of THSs will depend on the uptake of circulating Delta(4)-3-ketosteroids such as progesterone and testosterone. 3 alpha- and 3 beta-H5D 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 5 alpha,3 alpha-THSs enhance the effect of GABA on the GABA(A) receptor, whereas 5 alpha,3 beta-THSs are antagonists. (C) 2010 Elsevier B.V. All rights reserved.
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