Characterization of the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase complex in the human brain.
Although androgen metabolism in the human brain was discovered almost 30 yr ago, conclusive studies on the enzymes involved are still lacking. We therefore investigated 5alpha-reductase and colocalized 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity in cerebral neocortex (CX) and subcortical white matter (SC) specimens neurosurgically removed from 44 patients suffering from epilepsy. We could demonstrate the presence of the 5alpha-reductase-3alpha-HSD complex in the biopsies of all patients under investigation. Inhibition experiments with specific inhibitors for 5alpha-reductase type 1 and type 2 revealed strong evidence for the exclusive activity of the type 1 isoform. We detected a significantly higher 5alpha-reductase activity in CX than in SC (P< 0.0001), but no sex-specific differences were observed. Furthermore, we found that, in contrast to liver, only 3alpha-HSD type 2 messenger RNA is expressed in the brain and that its expression is significantly higher in SC than in CX without sex-specific differences. The present study is the first to systematically characterize the 5alpha-reductase-3alpha-HSD complex in the human brain. The lack of sex-specific differences and also the colocalization of both enzymes at all life stages suggest a more general purpose of the complex, e.g. the synthesis of neuroactive steroids or the catabolism of neurotoxic steroids, rather than control of reproductive functions.
Steckelbroeck
S
S
Department of Clinical Biochemistry, University of Bonn, 53105 Bonn, Germany. st_steckelbroeck@hotmail.com
Watzka
M
M
Reichelt
R
R
Hans
V H
VH
Stoffel-Wagner
B
B
Heidrich
D D
DD
Schramm
J
J
Bidlingmaier
F
F
Klingmüller
D
D
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D058891:5-alpha Reductase Inhibitors; D000293:Adolescent; D000328:Adult; D000368:Aged; D001378:Azasteroids / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000201:enzymology / Q000601:surgery; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D019579:Neocortex / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013702:Temporal Lobe / Q000201:enzymology / Q000648:ultrastructure; D014018:Tissue Distribution
C090665:4,7beta-dimethyl-4-azacholestan-3-one; D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D012333:RNA, Messenger; D018120:Finasteride; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase