Inhibition of aldosterone biosynthesis by staurosporine.
Staurosporine (STS) is a very potent broad-range kinase inhibitor, and its antiproliferative properties made it a lead compound for protein kinase C (PKC) inhibitors with therapeutic potential. Because STS also causes hypotension, we investigated in this study whether it directly interferes with the terminal steps of aldosterone biosynthesis; these are catalysed by a mitochondrial steroid hydroxylase system consisting of adrenodoxin reductase, adrenodoxin, and the cytochrome P450 enzyme hCYP11B2 (aldosterone synthase). Here we demonstrate that nanomolar concentrations of STS significantly reduced aldosterone synthase activity in transiently transfected COS-1 cells and in stably transfected V79MZh11B2 cells (IC50 = 11 nM). However, STS did not inhibit bovine aldosterone synthase in a reconstituted steroid hydroxylation assay. In transiently transfected COS-1 cells, the protein level of adrenodoxin (but not that of adrenodoxin reductase or of hCYP11B2) was significantly reduced after treatment with 2 nM STS. Finally, we show that STS treatment (1 microg/day) of mice reduced their aldosterone/renin ratio by almost 50% (p = 0.015). To the best of our knowledge, this is the first report of a direct in vivo effect of STS on the renin-angiotensin-aldosterone system. We conclude (i) that the hypotensive effect of staurosporine is at least partly due to inhibition of aldosterone biosynthesis via adrenodoxin depletion, and (ii) that aldosterone biosynthesis can be regulated in vivo at the level of adrenodoxin availability.
Bureik
Matthias
M
Department of Biochemistry, Saarland University, D-66041 Saarbrücken, Germany.
Mion
Alexander
A
Kenyon
Christopher J
CJ
Bernhardt
Rita
R
D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D019556:COS Cells; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019311:Staurosporine / Q000494:pharmacology*; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors; D014162:Transfection
D000450:Aldosterone; D013250:Steroid Hydroxylases; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D019311:Staurosporine