Adrenal androgen biosynthesis with special attention to P450c17.
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.
Mason
J I
JI
Department of Clinical Biochemistry, University of Edinburgh, Edinburgh Royal Infirmary NHS Trust, Scotland.
Bird
I M
IM
Rainey
W E
WE
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
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