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

Authors


  • This work is dedicated to Prof. Dr Dr Frank Bidlingmaier on the occasion of his 65th birthday.

Address correspondence and reprint requests to Stephan Steckelbroeck, Institut für Klinische Biochemie, Universitätsklinikum Bonn, Institut für Klinische Biochemie, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, D-53105 Bonn, Germany. E-mail: St_Steckelbroeck@hotmail.com

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 7α-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 µm, corresponding with the presence of the oxysterol 7α-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 17β-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 7α-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p < 0.0005), whereas in the subcortical white matter, 17β-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 7α-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.

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