Morphogenesis of a zone-specific adrenocortical cytotoxicity in guinea pigs administered PD 132301-2, an inhibitor of acyl-CoA:cholesterol acyltransferase (original) (raw)

PD 132301-2, a novel inhibitor of acyl-CoA:cholesterol acyltransferase, is adrenotoxic to several laboratory animal species. Morphogenesis of a zona fasciculata-specific cytotoxicity was evaluated in male Hartley guinea pigs administered 100 mg/kg of PD 132301-2 for up to 7 days. Reversibility of adrenal effects was assessed after a 14-day drug withdrawal period (day 21). Serum cortisol concentrations were determined under basal conditions and after administration of adrenocorticotrophic hormone (ACTH) on days 1, 2, 4, 7, and 21. Isolated foci of cortical cell degeneration and necrosis were apparent in outer zona fasciculata by 2 hr and throughout the zona fasciculata at 6 hr. Early degenerative ultrastructural changes included aggregation of smooth endoplasmic reticulum (SER), variable condensation of mitochondrial matrices and swelling of cristae, partitioning of organelles, autophagosome formation, and disruption of lipid globules. Lesions progressed to locally extensive or diffu...