title: Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regulation of CYP7B1-mediated metabolism.
abstract: The neurosteroid dehydroepiandrosterone (DHEA) is formed locally in the CNS and has been implicated in several processes essential for CNS function, including control of neuronal survival. An important metabolic pathway for DHEA in the CNS involves the steroid hydroxylase CYP7B1. In previous studies, CYP7B1 was identified as a target for estrogen regulation in cells of kidney and liver. In the current study, we examined effects of estrogens on CYP7B1-mediated metabolism of DHEA in primary cultures of rat astrocytes and co-cultures of rat CNS cells. Astrocytes, which interact with neurons in several ways, are important for brain neurosteroidogenesis. We found that estradiol significantly suppressed CYP7B1-mediated DHEA hydroxylation in primary mixed CNS cultures from fetal and newborn rats. Also, CYP7B1-mediated DHEA hydroxylation and CYP7B1 mRNA were markedly suppressed by estrogen in primary cultures of rat astrocytes. Interestingly, diarylpropionitrile, a well-known agonist of estrogen receptor β, also suppressed CYP7B1-mediated hydroxylation of DHEA. Several previous studies have reported neuroprotective effects of estrogens. The current data indicate that one of the mechanisms whereby estrogen can exert protective effects in the CNS may involve increase of the levels of DHEA by suppression of its metabolism.
authors.affiliation: Departments of Neuroscience, University of Uppsala, Sweden.
authors.forename: Asa
authors.initials: A
authors.lastname: Fex Svenningsen
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Wicher
authors.forename: Johan
authors.initials: J
authors.lastname: Lundqvist
authors.forename: Hanna
authors.initials: H
authors.lastname: Pettersson
authors.forename: Mikael
authors.initials: M
authors.lastname: Corell
authors.forename: Maria
authors.initials: M
authors.lastname: Norlin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D018920:Coculture Techniques; D000072474:Cytochrome P450 Family 7; D017931:DNA Primers; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D006900:Hydroxylation; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D009570:Nitriles; D012333:RNA, Messenger; D003687:Dehydroepiandrosterone; D004958:Estradiol; C005557:propionitrile; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C490784:Cyp7b1 protein, rat