Adrenal cortical 11 beta-hydroxylase and side-chain cleavage enzymes. Requirement for the A- or B-pyridyl ring in metyrapone for inhibition.
The adrenal cortical enzyme systems, 11 beta-hydroxylase, P-450 11 beta, and the side-chain cleavage complex, P-450 scc, differ only in their cytochrome P-450s. Structural modifications of metyrapone, an inhibitor of cytochrome P-450 enzyme systems, have been made to determine the requirement for the A- or B-pyridyl ring for inhibition of P-45011 beta and P-450 scc activities. Three new analogs of metyrapone (A-phenylmetyrapone, B-phenylmetyrapone and diphenylmetyrapone) were synthesized and evaluated as inhibitors using a crude, defatted bovine adrenal cortical mitochondrial preparation. Characterization of the mitochondrial preparation demonstrated: enhancement of both activities by the addition of 15.0 microM adrenodoxin, the addition of 1% ethanol decreased both activities less than 10%, and the apparent Km of deoxycorticosterone for P-45011 beta was 6.8 microM and the apparent Km of cholesterol for P-450 scc was 21.6 microM. Inhibition of P-45011 beta and P-450 scc activities with these compounds demonstrated: the B-pyridyl ring of metyrapone is required for inhibition of both activities whereas requirement for the A-ring is less stringent, and the four metyrapone analogs were more selective inhibitors of P-45011 beta activity. These studies suggest that the A-phenyl metyrapone analog is a good candidate for further development of a selective adrenocortical radiopharmaceutical.
D000302:Adrenal Cortex / Q000201:enzymology*; D000325:Adrenodoxin / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D065607:Cytochrome P-450 Enzyme Inhibitors; D007700:Kinetics; D008797:Metyrapone / Q000031:analogs & derivatives* / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology; D012997:Solvents; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D012997:Solvents; D000325:Adrenodoxin; C044813:2-methyl-1,2-diphenyl-1-propanone; C044814:2-methyl-1-phenyl-2-(3-pyridinyl)-1-propanone; D013250:Steroid Hydroxylases; D013252:Steroid 11-beta-Hydroxylase; D008797:Metyrapone