A new 21-aminosteroid antioxidant lacking glucocorticoid activity stimulates adrenocorticotropin secretion and blocks arachidonic acid release from mouse pituitary tumor (AtT-20) cells.
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.
Braughler
J M
JM
CNS Diseases Research Unit, Upjohn Company, Kalamazoo, Michigan.
Chase
R L
RL
Neff
G L
GL
Yonkers
P A
PA
Day
J S
JS
Hall
E D
ED
Sethy
V H
VH
Lahti
R A
RA
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D010911:Pituitary Neoplasms / Q000378:metabolism*; D011281:Pregnatrienes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D001095:Arachidonic Acids; D005938:Glucocorticoids; D008054:Lipid Peroxides; D011281:Pregnatrienes; D014810:Vitamin E; D016718:Arachidonic Acid; D000324:Adrenocorticotropic Hormone; C053355:tirilazad