title: Effect of n-3 and n-6 Polyunsaturated Fatty Acids on Microsomal P450 Steroidogenic Enzyme Activities and In Vitro Cortisol Production in Adrenal Tissue From Yorkshire Boars.
abstract: Dysregulation of adrenal glucocorticoid production is increasingly recognized to play a supportive role in the metabolic syndrome although the mechanism is ill defined. The adrenal cytochrome P450 (CYP) enzymes, CYP17 and CYP21, are essential for glucocorticoid synthesis. The omega-3 and omega-6 polyunsaturated fatty acids (PUFA) may ameliorate metabolic syndrome, but it is unknown whether they have direct actions on adrenal CYP steroidogenic enzymes. The aim of this study was to determine whether PUFA modify adrenal glucocorticoid synthesis using isolated porcine microsomes. The enzyme activities of CYP17, CYP21, 11β-hydroxysteroid dehydrogenase type 1, hexose-6-phosphate dehydrogenase (H6PDH), and CYP2E1 were measured in intact microsomes treated with fatty acids of disparate saturated bonds. Cortisol production was measured in a cell-free in vitro model. Microsomal lipid composition after arachidonic acid (AA) exposure was determined by sequential window acquisition of all theoretical spectra-mass spectrometry. Results showed that adrenal microsomal CYP21 activity was decreased by docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), eicosapentaenoic acid, α-linolenic acid, AA, and linoleic acid, and CYP17 activity was inhibited by DPA, DHA, eicosapentaenoic acid, and AA. Inhibition was associated with the number of the PUFA double bonds. Similarly, cortisol production in vitro was decreased by DPA, DHA, and AA. Endoplasmic enzymes with intraluminal activity were unaffected by PUFA. In microsomes exposed to AA, the level of AA or oxidative metabolites of AA in the membrane was not altered. In conclusion, these observations suggest that omega-3 and omega-6 PUFA, especially those with 2 or more double bonds (DPA, DHA, and AA), impede adrenal glucocorticoid production.
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xie
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Mick
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Janusz H
authors.initials: JH
authors.lastname: Kabarowski
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Landon Shay
authors.initials: LS
authors.lastname: Wilson
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Stephen
authors.initials: S
authors.lastname: Barnes
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Walcott
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Luo
authors.affiliation: Departments of Pediatrics (X.X., X.W., G.J.M., K.M.), Microbiology (J.H.K.), Pharmacology and Toxicology (L.S.W., S.B.), and Cardiovascular Disease (G.P.W.), University of Alabama at Birmingham, Birmingham, Alabama 35233; Department of Pediatrics (X..X., X.L.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; and Department of Endocrinology and Metabolism (X.X.), Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541004, China.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McCormick
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6 / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006854:Hydrocortisone / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013552:Swine
chemical_list: D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D005231:Fatty Acids, Unsaturated; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D019392:Cytochrome P-450 CYP2E1; D013254:Steroid 17-alpha-Hydroxylase; C026219:docosapentaenoic acid; D006854:Hydrocortisone