AMINOGLUTETHIMIDE AND GLUTETHIMIDE: EFFECTS ON 18-HYDROXYCORTICOSTERONE BIOSYNTHESIS BY HUMAN AND SHEEP ADRENALS IN VITRO

Abstract

ABSTRACT The conversion of [1,2-3H] corticosterone to 18-hydroxycorticosterone in vitro was studied on human and animal adrenal tissue homogenates. Human adrenals were surgically resected from a patient with Cushing's disease. Sheep adrenal homogenates were prepared from the pooled glands of 20 animals. Incubations supplemented with a NADPH generating system were performed in order to evaluate the effect of aminoglutethimide and its closely related compound glutethimide on corticosterone 18-hydroxylation in vitro. Increasing concentrations of the two drugs were assayed on both human and animal adrenal homogenates. Aminoglutethimide was clearly found to inhibit corticosterone 18-hydroxylation in sheep adrenal homogenates as a 72.6 % inhibition occurred in the presence of only 0.2 μmole of the drug. Inhibition reached 91.1 % in the presence of 0.5 μmole aminoglutethimide. When added to the human incubated adrenal, a 59.4 % inhibition occurred in the presence of 0.5 μmole aminoglutethimide. Glutethimide, a sedative of wide clinical usage, was also found to inhibit corticosterone 18-hydroxylation but the inhibitory effect occurred only in the presence of much higher concentrations. In fact, 5.0 μmoles were necessary to obtain a 43.9% inhibition of 18-hydroxycorticosterone synthesis. This study clearly demonstrates the marked inhibitory effect of aminoglutethimide on corticosterone 18-hydroxylation. Glutethimide, to a lesser extent, also inhibits 18-hydroxycorticosterone synthesis.