Response of adrenal tumor cells to adrenocorticotropin: site of inhibition by cytochalasin B.
The ability of cytochalasin B to inhibit the steroidogenic response of mouse adrenal tumor cells (Y-1) to adrenocorticotropin (ACTH) was examined with two aims: to consider the specificity of the inhibitor and to determine at what point(s) in the steroidogenic pathway it acts. Cytochalasin B did not inhibit protein synthesis or transport of [3H]-cholesterol into the cells nor did it alter total cell concentration of ATP. Together with previous evidence, this suggests that the effects of cytochalasin observed are relatively specific in these cells. Cytochalasin inhibits the increase in conversion of [3H]cholesterol to 20alpha-[3H]dihydroprogesterone (20alpha-hydroxypregn-4-en-3-one: a major product of the steroid pathway in Y-1 cells) produced by ACTH but does not inhibit conversion of cholesterol to pregnenolone by mitochondrial and purified enzyme preparations from Y-1 cells and bovine adrenal, respectively. Cytochalasin does not inhibit the conversion of pregnenolone to 20alpha-dihydroprogesterone but was shown to inhibit increased transport of [3H]cholesterol to mitochondria resulting from the action of ACTH. These findings indicate that cytochalasin acts after cholesterol has entered the cells and before it is subjected to side-chain cleavage in mitochondria. In view of the known action of cytochalasin on microfilaments, it is proposed that these organelles are necessary for the transport of cholesterol to the mitochondrial cleavage enzyme and that at least one effect of ACTH (and cyclic AMP) is exerted upon this transport process. The specificity of the effects of cytochalasin is considered in relation to this conclusion.
D004092:20-alpha-Dihydroprogesterone / Q000096:biosynthesis*; D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011284:Pregnenolone / Q000096:biosynthesis; D011374:Progesterone / Q000031:analogs & derivatives*; D014176:Protein Biosynthesis
D000616:Aminoglutethimide; D004092:20-alpha-Dihydroprogesterone; D003571:Cytochalasin B; D011374:Progesterone; D003994:Bucladesine; D011284:Pregnenolone; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol