MORPHOGENESIS OF A ZONE-SPECIFIC ADRENOCORTICAL CYTOTOXICITY IN GUINEA-PIGS ADMINISTERED PD-132301-2, AN INHIBITOR OF ACYL-COA - CHOLESTEROL ACYLTRANSFERASE

PD 132301-2, a novel inhibitor of acyl-CoA: cholesterol acyltransferas e, is adrenotoxic to several laboratory animal species. Morphogenesis of a zona fasciculata-specific cytotoxicity was evaluated in male Hart ley 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 wi thdrawal period (day 21). Serum cortisol concentrations were determine d under basal conditions and after administration of adrenocorticotrop hic hormone (ACTH) on days 1, 2, 4, 7, and 21. Isolated foci of cortic al cell degeneration and necrosis were apparent in outer zona fascicul ata by 2 hr and throughout the zona fasciculata at 6 hr. Early degener ative ultrastructural changes included aggregation of smooth endoplasm ic reticulum (SER), variable condensation of mitochondrial matrices an d swelling of cristae, partitioning of organelles, autophagosome forma tion, and disruption of lipid globules. Lesions progressed to locally extensive or diffuse zonal necrosis on days 1 and 2 and near complete ablation of zona fasciculata by day 4. Fasciculata cells remaining on day 4 had reduced numbers and increased size of lipid globules, increa sed lysosomes, and, occasionally, aggregates of SER and mitochondria. On day 7, SER proliferation and lipid depletion were apparent in remai ning cells. ACTH responses were attenuated 24 hr after the first dose, and reduction in basal cortisol levels were seen by 24 hr after the s econd dose with both effects maximal on day 7. After a 14-day withdraw al period, ACTH responses and adrenal morphology returned to normal. I t was concluded that PD 132301-2 induced rapid, reversible, zone-speci fic, morphologic, and functional adrenocortical effects. Furthermore, mitochondria and SER represented early subcellular targets of toxicity .