title: Regulation of human 3β-hydroxysteroid dehydrogenase type 2 by adrenal corticosteroids and product-feedback by androstenedione in human adrenarche.
abstract: In human adrenarche during childhood, the secretion of dehydroepiandrosterone (DHEA) from the adrenal gland increases due to its increased synthesis and/or decreased metabolism. DHEA is synthesized by 17α-hydroxylase/17,20-lyase, and is metabolized by 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2). In this study, the inhibition of purified human 3βHSD2 by the adrenal steroids, androstenedione, cortisone, and cortisol, was investigated and related to changes in secondary enzyme structure. Solubilized, purified 3βHSD2 was inhibited competitively by androstenedione with high affinity, by cortisone at lower affinity, and by cortisol only at very high, nonphysiologic levels. When purified 3βHSD2 was bound to lipid vesicles, the competitive Ki values for androstenedione and cortisone were slightly decreased, and the Ki value of cortisol was decreased 2.5-fold, although still at a nonphysiologic level. The circular dichroism spectrum that measured 3βHSD2 secondary structure was significantly altered by the binding of cortisol, but not by androstenedione and cortisone. Our import studies show that 3βHSD2 binds in the intermitochondrial space as a membrane-associated protein. Androstenedione inhibits purified 3βHSD2 at physiologic levels, but similar actions for cortisol and cortisone are not supported. In summary, our results have clarified the mechanisms for limiting the metabolism of DHEA during human adrenarche.
authors.affiliation: Division of Basic Medical Sciences (J.L.T., V.L.M.) and Department of Ob-Gyn (J.L.T.), Mercer University School of Medicine, Macon, Georgia; Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia (M.R., G.A.D., H.S.B.); Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (H.S.B.); and Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.A.M.) thomas_j@mercer.edu.
authors.forename: James L
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Division of Basic Medical Sciences (J.L.T., V.L.M.) and Department of Ob-Gyn (J.L.T.), Mercer University School of Medicine, Macon, Georgia; Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia (M.R., G.A.D., H.S.B.); Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (H.S.B.); and Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.A.M.).
authors.forename: Maheshinie
authors.initials: M
authors.lastname: Rajapaksha
authors.affiliation: Division of Basic Medical Sciences (J.L.T., V.L.M.) and Department of Ob-Gyn (J.L.T.), Mercer University School of Medicine, Macon, Georgia; Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia (M.R., G.A.D., H.S.B.); Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (H.S.B.); and Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.A.M.).
authors.forename: Vance L
authors.initials: VL
authors.lastname: Mack
authors.affiliation: Division of Basic Medical Sciences (J.L.T., V.L.M.) and Department of Ob-Gyn (J.L.T.), Mercer University School of Medicine, Macon, Georgia; Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia (M.R., G.A.D., H.S.B.); Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (H.S.B.); and Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.A.M.).
authors.forename: Geneva A
authors.initials: GA
authors.lastname: DeMars
authors.affiliation: Division of Basic Medical Sciences (J.L.T., V.L.M.) and Department of Ob-Gyn (J.L.T.), Mercer University School of Medicine, Macon, Georgia; Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia (M.R., G.A.D., H.S.B.); Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (H.S.B.); and Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.A.M.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Majzoub
authors.affiliation: Division of Basic Medical Sciences (J.L.T., V.L.M.) and Department of Ob-Gyn (J.L.T.), Mercer University School of Medicine, Macon, Georgia; Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia (M.R., G.A.D., H.S.B.); Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (H.S.B.); and Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.A.M.).
authors.forename: Himangshu S
authors.initials: HS
authors.lastname: Bose
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D050499:Adrenarche / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D000735:Androstenedione / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003348:Cortisone / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D025461:Feedback, Physiological / Q000187:drug effects*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000494:pharmacology; D008081:Liposomes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D021381:Protein Transport / Q000187:drug effects; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; D008081:Liposomes; D000735:Androstenedione; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D003348:Cortisone; D006854:Hydrocortisone