Characterisation of estrogenic 17β-hydroxysteroid dehydrogenase (17β-HSD) activity in the human brain

Abstract

Estrogens play a crucial role in multiple functions of the brain and the proper balance of inactive estrone and active estradiol-17β might be very important for their cerebral effects. The interconversion of estrone and estradiol-17β in target tissues is known to be catalysed by a number of human 17β-hydroxysteroid dehydrogenase (17β-HSD) isoforms. The present study shows that enzyme catalysed interconversion of estrone and estradiol-17β occurs in the human temporal lobe. The oxidative cerebral pathway preferred estradiol-17β to Δ 5-androstenediol and testosterone, whereas the reductive pathway preferred dehydroepiandrosterone (DHEA) to Δ 4-androstenedione and estrone. An allosteric Hill kinetic for NAD-dependent oxidation of estradiol-17β was observed, whereas a typical Michaelis–Menten kinetic was shown for NADPH-dependent reduction of estrone. Investigations of the interconversion of estrogens in cerebral neocortex (CX) and subcortical white matter (SC) preparations of brain tissue from 12 women and 10 men revealed no sex-differences, but provide striking evidence for the presence of at least one oxidative membrane-associated 17β-HSD and one cytosolic enzyme that catalyses both the reductive and the oxidative pathway. Membrane-associated oxidation of estradiol-17β was shown to be significantly higher in CX than in SC ( P<0.05), whereas the cytosolic enzyme activities were significantly higher in SC than in CX ( P<0.0005). Finally, real-time RT-PCR analyses revealed that besides 17β-HSD types 4 and 5 also the isozymes type 7, 8, 10 and 11 show substantial expression in the human temporal lobe. The characteristics of the isozymes lead us to the conclusion that cytosolic 17β-HSD type 5 is the best candidate for the observed cytosolic enzyme activities, whereas the data gave no clear answer to the question, which enzyme is responsible for the membrane-associated oxidation of estradiol-17β. In conclusion, the study strongly suggests that different cell types and different isozymes are involved in the cerebral interconversion of estrogens, which might play a pivotal role in maintaining the functions of the central nervous system.