Effect of 4-Aminopyrazolopyrimidine and Aminoglutethimide on Cholesteryl Metabolism and Steroidogenesis in the Rat Adrenal*

Abstract

The interrelationship between adrenal cholesteryl ester metabolism and steroidogenesis was examined by using 4-aminopyrazolopyrimidine (4-APP) and aminoglutethimide under in vivo and in vitro conditions. In vivo administration of 4-APP resulted in a reduction of plasma corticosterone and a diminished steroidogenic response to injected ACTH. After a 4 day recovery from 4-APP treatment, basal corticosterone levels remained low, but responsiveness to ACTH administration was observed. These steroidogenic effects were correlated with changes in plasma and adrenal cholesterol concentrations. Administration of aminoglutethimide prevented depletion of adrenal cholesteryl esters which occurred in response to 4-APP treatment alone and also prevented the stress-induced cholesteryl ester depletion in response to unilateral adrenalectomy. Adrenal cell suspensions were used to study further the effect of aminoglutethimide and 4-APP on adrenal cholesterol metabolism. Suspensions prepared from 4-APP-treated animals were less responsive to ACTH with respect to corticosterone production than cells from control animals, and the net incorporation of oleic acid into cholesteryl ester, used as an indicator of cholesteryl ester synthesis, also was reduced in cells from treated animals. Cells from aminoglutethimide-treated animals had greater than control rates of steroidogenesis, but similar rates of cholesteryl ester synthesis as control cells. Direct addition of aminoglutethimide to cell suspensions produced increased oleate incorporation into cholesteryl ester and diminished steroidogenesis in all preparations studied. These data further document the effects of 4-APP and aminoglutethimide on adrenal cholesterol metabolism and suggest that the regulation of adrenal cholesteryl ester metabolism is closely associated with the regulation of steroidogenesis.