title: Adrenal androgen biosynthesis with special attention to P450c17.
abstract: In vitro studies of human adrenal androgen synthesis are limited because of the difficulties in obtaining adrenals. We describe the use of the human adrenocortical tumor H295 cell line as a model to evaluate mechanisms controlling C19-steroid production. The cells were characterized with regard to responsiveness to a variety of agents as measured by steroid secretion and induction of 17 alpha-hydroxylase cytochrome P450 (P450c17) expression, a key enzyme in C19-steroid production. Forskolin and dibutyryl cAMP, which were more effective than ACTH, enhanced the production of DHEA and androstenedione over a 48-hour treatment period. Agents that act by increasing intracellular calcium (angiotensin II and K+ ions) as well as protein kinase A pathway activators (ACTH, forskolin, and dibutyryl cAMP) individually increased the mRNA levels and activity of P450c17. In addition, angiotensin II but not K+ ions attenuated the increased expression promoted by the kinase A agonists. Thus, the complexity of human adrenal P450c17 expression through multiple signaling pathways may contribute importantly to the diverse patterns of human adrenocortical steroidogenesis.
authors.affiliation: Department of Clinical Biochemistry, University of Edinburgh, Edinburgh Royal Infirmary NHS Trust, Scotland.
authors.forename: J I
authors.initials: JI
authors.lastname: Mason
authors.forename: I M
authors.initials: IM
authors.lastname: Bird
authors.forename: W E
authors.initials: WE
authors.lastname: Rainey
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism; D000446:Aldehyde-Lyases / Q000235:genetics; D000450:Aldosterone / Q000096:biosynthesis; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D019314:Dehydroepiandrosterone Sulfate; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D008969:Molecular Sequence Data; D013254:Steroid 17-alpha-Hydroxylase; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; D005576:Colforsin; D003687:Dehydroepiandrosterone; D000450:Aldosterone; D019314:Dehydroepiandrosterone Sulfate; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D015096:3-Hydroxysteroid Dehydrogenases; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D000446:Aldehyde-Lyases; D002118:Calcium; D006854:Hydrocortisone