Spironolactone inhibition of cortisol production by guinea pig adrenocortical cells.
Prior investigations with adrenal subcellular fractions demonstrated that the diuretic, spironolactone (SL), was converted to a reactive metabolite by adrenal microsomes, resulting in the degradation of microsomal cytochrome(s) P-450. Studies were done to evaluate the effects of SL and 7 alpha-thio-SL, a putative intermediate in the activation pathway, on cortisol production by intact guinea pig adrenocortical cells. Preincubation of adrenal cells with SL or 7 alpha-thio-SL caused time-dependent and concentration-dependent decreases in subsequent ACTH-stimulated cortisol production. 7 alpha-Thio-SL was a far more potent inhibitor than SL. In the absence of a preincubation period, neither SL nor 7 alpha-thio-SL affected cortisol production. The results indicate that the effects of SL on adrenal microsomal cytochrome(s) P-450 compromise steroid synthesis by intact adrenal cells and lend support to the hypothesis that metabolism of the drug is required for the inhibition of steroidogenesis.
Rourke
K A
KA
Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, Pennsylvania.
Colby
H D
HD
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000096:biosynthesis*; D007700:Kinetics; D008297:Male; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology*
D013148:Spironolactone; C033554:7 alpha-thiospironolactone; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; D006854:Hydrocortisone