A new 21-aminosteroid antioxidant lacking glucocorticoid activity stimulates adrenocorticotropin secretion and blocks arachidonic acid release from mouse pituitary tumor (AtT-20) cells

Abstract

The compound U74006F (21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methyl- pregna-1,4,9(11)-triene-3,20-dione) is one of a novel series of 21-aminosteroids that are potent inhibitors of iron-dependent lipid peroxidation. Chronic (4-6 days) dosing of mice or rats with high doses of U74006F (30-200 mg/kg/day) has indicated that the compound is devoid of both glucocorticoid and mineralocorticoid activity. Although the compound is not a glucocorticoid antagonist, it markedly stimulated secretion of adrenocorticotropin by the murine pituitary tumor (AtT-20) cell. The enhanced secretion of adrenocorticotropin was not associated with an increased incorporation of [3H]thymidine or [14C]leucine into DNA or protein, respectively. Although not a glucocorticoid, U74006F also blocked the release of [14C]arachidonic acid from AtT-20 cells damaged by either Fe++ or the metabolic poison, iodoacetate. U74006F represents a novel class of antioxidant which displays cytoprotective activity and may uniquely affect cell growth or function in culture systems.