title: C21-steroids inactivation and glucocorticoid synthesis in the developing lung.
abstract: Glucocorticoids (GCs) are important regulators of lung development. The genes normally involved in GC synthesis in adrenals are co-expressed with 20α-hydroxysteroid dehydrogenase (20α-HSD) in the developing lung. In this study, C21-steroid metabolism was investigated in fetal and postnatal mouse lungs. Incubation of [(3)H]-progesterone with lung explant cultures of different perinatal developmental time points revealed two different (antenatal vs. postnatal) complex metabolization patterns. Progesterone inactivation was predominant. 20αOH-derivatives were more abundant after birth and some metabolites were 5α-reduced. Using [(3)H]-progesterone as substrate, corticosterone synthesis was only observed in a fraction of lung explants from gestation day (GD) 15.5. Neither aldosterone synthase nor P450c17 activity was observed. With epithelial-enriched primary cell cultures, deoxycorticosterone synthesis from [(3)H]-progesterone was observed. With lung explants incubated with [(3)H]-corticosterone as substrate, [(3)H]-4-pregnen-21-ol-3,11,20-trione (11-dehydrocorticosterone), the product of 11β-HSD2, accumulated in higher proportion on GD 15.5 than at later developmental time points. The temporal correlation observed between levels of progesterone inactivation by 20α-HSD (higher after birth) and the sensitivity of lung development to GCs suggests a role for 20α-HSD in the modulation of GR occupancy through the control of 21-hydroxylase substrate and product levels. In conclusion, the developing lung is characterized by effective inactivation of c21-steroids by 20α-HSD. The formation of active GCs from the "adrenal"-like pathway was observed with some lung explants and primary epithelial cell cultures. Coexistence of this GC synthesis pathway with 20α-HSD activity strongly suggests local regulation of GC action and is compatible with intracrine/paracrine actions of GC.
authors.affiliation: Reproduction, Mother and Youth Health, Centre de recherche du CHU de Québec, Québec, QC, Canada; Centre de Recherche en Biologie de la Reproduction (CRBR), Faculty of Medicine, Laval University, Québec, QC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Boucher
authors.affiliation: Reproduction, Mother and Youth Health, Centre de recherche du CHU de Québec, Québec, QC, Canada; Department of Obstetrics/Gynecology & Reproduction, Faculty of Medicine, Laval University, Québec, QC, Canada; Centre de Recherche en Biologie de la Reproduction (CRBR), Faculty of Medicine, Laval University, Québec, QC, Canada.
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Provost
authors.affiliation: Reproduction, Mother and Youth Health, Centre de recherche du CHU de Québec, Québec, QC, Canada; Department of Obstetrics/Gynecology & Reproduction, Faculty of Medicine, Laval University, Québec, QC, Canada; Centre de Recherche en Biologie de la Reproduction (CRBR), Faculty of Medicine, Laval University, Québec, QC, Canada. Electronic address: yves.tremblay@crchudequebec.ulaval.ca.
authors.forename: Yves
authors.initials: Y
authors.lastname: Tremblay
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D043607:20-alpha-Hydroxysteroid Dehydrogenase / Q000378:metabolism; D000818:Animals; D053898:Biosynthetic Pathways; D002478:Cells, Cultured; D003345:Corticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D008168:Lung / Q000254:growth & development* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D011374:Progesterone / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D013256:Steroids; D011374:Progesterone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D043607:20-alpha-Hydroxysteroid Dehydrogenase; D013255:Steroid 21-Hydroxylase; C003552:11-dehydrocorticosterone; D003345:Corticosterone
keywords: 11β-HSD; 11β-Hydroxylase; 20α-HSD; 21-Hydroxylase; Corticosterone; Intracrine; Mineralocorticoid; Paracrine; Progesterone; Steroidogenesis