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Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reductase activity in the human brain.
- Source :
-
Journal of neurochemistry [J Neurochem] 2002 Nov; Vol. 83 (3), pp. 713-26. - Publication Year :
- 2002
-
Abstract
- Dehydroepiandrosterone and its sulphate are important factors for vitality, development and functions of the CNS. They were found to be subjects to a series of enzyme-mediated conversions within the rodent CNS. In the present study, we were able to demonstrate for the first time that membrane-associated dehydroepiandrosterone 7alpha-hydroxylase activity occurs within the human brain. The cytochrome P450 enzyme demonstrated a sharp pH optimum between 7.5 and 8.0 and a mean KM value of 5.4 micro m, corresponding with the presence of the oxysterol 7alpha-hydroxylase CYP7B1. Real-time RT-PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS. The additionally observed conversion of dehydroepiandrosterone via cytosolic 17beta-hydroxysteroid dehydrogenase activity could be ascribed to the activity of an enzyme with a broad pH optimum and an undetectably high KM value. Subsequent experiments with cerebral neocortex and subcortical white matter specimens revealed that 7alpha-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p < 0.0005), whereas in the subcortical white matter, 17beta-hydroxysteroid dehydrogenase activity is significantly higher than in the cerebral neocortex (p < 0.0005). No sex differences were observed. In conclusion, the high levels of CYP7B1 mRNA in brain tissue as well as in a variety of other tissues in combination with the ubiquitous presence of 7alpha-hydroxylase activity in the human temporal lobe led us to assume a neuroprotective function of the enzyme such as regulation of the immune response or counteracting the deleterious effects of neurotoxic glucocorticoids, rather than a distinct brain specific function such as neurostimulation or neuromodulation.
- Subjects :
- Adolescent
Adult
Aged
Animals
Brain Chemistry
Child
Child, Preschool
Chromatography, Thin Layer
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System genetics
Cytochrome P450 Family 7
Dehydroepiandrosterone chemistry
Enzyme Activation drug effects
Enzyme Activation physiology
Enzyme Inhibitors pharmacology
Female
Gas Chromatography-Mass Spectrometry
Humans
Hydrogen-Ion Concentration
Infant
Male
Mice
Mice, Inbred C57BL
Middle Aged
NADP metabolism
Organ Specificity
RNA, Messenger analysis
RNA, Messenger metabolism
Rats
Rats, Wistar
Steroid Hydroxylases antagonists & inhibitors
Steroid Hydroxylases genetics
Temporal Lobe chemistry
Temporal Lobe metabolism
17-Hydroxysteroid Dehydrogenases metabolism
Brain metabolism
Cytochrome P-450 Enzyme System metabolism
Dehydroepiandrosterone metabolism
Steroid Hydroxylases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3042
- Volume :
- 83
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12390533
- Full Text :
- https://doi.org/10.1046/j.1471-4159.2002.01187.x