The effect of polymyxin B on steroidogenesis from adrenocortical cells.
The action of the cyclic peptide polymyxin B (a well known inhibitor of protein kinase C) on adrenal steroid synthesis was examined with Y-1 adrenal tumor cells. Polymyxin B produces a biphasic effect on the stimulation of steroid synthesis by 2 nM ACTH in these cells, with inhibition at low concentrations (less than 10 microM) and a return to control levels at high concentrations (greater than 100 microM). Polymyxin B does not inhibit the stimulatory effect of Bu2cAMP on steroidogenesis. Inhibition of the steroidogenic response to ACTH by a fixed concentration (20 microM) of polymyxin B is overcome by high concentrations of ACTH. Polymyxin B causes a concentration-dependent stimulation of steroid synthesis by Y-1 cells and, over the same concentration range, increases the production of cAMP by these cells. Polymyxin B also partially inhibits the increased production of the cyclic nucleotide produced by ACTH. In addition, polymyxin B inhibits binding of [125I](Phe2,Nle4)ACTH-(1-38) to Y-1 cells. Polymyxin B, like ACTH, promotes rounding of Y-1 cells and partially inhibits rounding produced by ACTH. These effects of polymyxin B are specific to the extent that polymyxins E1 and E2 do not exert similar effects. The actions of polymyxin B are not confined to transformed cells, since responses similar to those seen with Y-1 cells were also observed with cultured rat fasciculata cells. On the other hand, the effect of polymyxin B is specific for adrenal cells, since the cyclic peptide does not influence the steroidogenic response of rat Leydig cells to LH. It is concluded that polymyxin B is a partial agonist of ACTH which is likely to prove useful in studying the molecular basis of the interaction between ACTH and its adrenal receptor.
D004092:20-alpha-Dihydroprogesterone / Q000096:biosynthesis; D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D051379:Mice; D010446:Peptide Fragments; D011112:Polymyxin B / Q000494:pharmacology*; D011113:Polymyxins / Q000494:pharmacology*; D051381:Rats; D013739:Testosterone / Q000096:biosynthesis
D000305:Adrenal Cortex Hormones; D010446:Peptide Fragments; D011113:Polymyxins; D004092:20-alpha-Dihydroprogesterone; D013739:Testosterone; D003994:Bucladesine; C030701:ACTH (1-38), Phe(2)-Nle(4)-; D000324:Adrenocorticotropic Hormone; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D011112:Polymyxin B