title: Estrone formation from dehydroepiandrosterone in cultured human breast adipose stromal cells.
abstract: The metabolism of dehydroepiandrosterone (DHA) and androstenedione (A-dione) was studied in cultured human adipose stromal cells obtained from breast tissue of six premenopausal patients undergoing reduction mammoplasty. Cells were maintained in culture in the presence of 10% fetal bovine serum. Studies were carried out during the proliferative and confluent phases of culture with radiolabelled substrates (2 microCi, 10 nM). During the early phases of replication 7 alpha-hydroxydehydroepiandrosterone (7 alpha-OHDHA) was formed from DHA. As the cells reached confluence, the major metabolite of DHA in cells from all patients was A-dione indicating the presence of 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD). The conversion of DHA to A-dione was variable among patients when cells were confluent with 30-80% of substrate being metabolized to this product. Adipose stromal cells synthesized estrone (E1) from DHA once A-dione formation was established. Under basal conditions E1 was obtained in cells from three of the six patients examined with up to 36% substrate converted to this product. Dexamethasone (Dex 10(-7) M) stimulated E1 formation in cells from all subjects with up to 50% of substrate being converted. Parallel studies comparing the conversion of DHA with A-dione to E1 revealed that as the cells became confluent, E1 formation from both substrates was similar. The pattern of steroid metabolism was also examined in primary culture and in subculture. Passage 1 cells continued to form A-dione as a major metabolite of DHA, and did not revert to the pattern of metabolism found in primary cells during the early stages of replication, when 7 alpha-hydroxylation predominated. Human adipose stromal cells actively metabolize DHA, producing 7 alpha-OHDHA, A-dione and E1 as principal metabolites. Changes in the circulating levels of DHA may directly influence the formation of E1 in peripheral tissues. This source of E1 will be modulated by factors controlling 3 beta-HSD and aromatase activities.
authors.affiliation: Lawson Research Institute, University of Western Ontario, London, Canada.
authors.forename: D W
authors.initials: DW
authors.lastname: Killinger
authors.forename: B J
authors.initials: BJ
authors.lastname: Strutt
authors.forename: D A
authors.initials: DA
authors.lastname: Roncari
authors.forename: M W
authors.initials: MW
authors.lastname: Khalil
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000735:Androstenedione / Q000378:metabolism; D001940:Breast / Q000166:cytology; D002455:Cell Division; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004970:Estrone / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008875:Middle Aged; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D004970:Estrone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D003907:Dexamethasone