Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reductase activity in the human brain

• Published in: Journal of neurochemistry 2002-11, Vol.83 (3), p.713
• Main Authors: Steckelbroeck, Stephan, Watzka, Matthias, Lütjohann, Dieter, Makiola, Paul, Nassen, Alexander, Hans, Volkmar H J, Clusmann, Hans, Reissinger, Annette, Ludwig, Michael, Siekmann, Lothar, Klingmüller, Dietrich
• Format: Article
• Language: English
• Subjects: 17-Hydroxysteroid Dehydrogenases - metabolism; Adolescent; Adult; Aged; Animals; Brain - metabolism; Brain Chemistry; Child; Child, Preschool; Chromatography, Thin Layer; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 Family 7; Dehydroepiandrosterone - chemistry; Dehydroepiandrosterone - metabolism; 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; Rats; Rats, Wistar; RNA, Messenger - analysis; RNA, Messenger - metabolism; Steroid Hydroxylases - antagonists & inhibitors; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Temporal Lobe - chemistry; Temporal Lobe - metabolism
• ISSN: 0022-3042

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.