Pathological features of the recovery phase in drug-induced vacuolar lesions caused by steroidogenesis disruption in the canine adrenal cortex

Steroidogenesis disruption caused by compounds causes vacuolar lesions in the adrenal cortex. However, research on the reversibility of compound-induced adrenal lesions remains limited. In a 4-week oral repeated-dose toxicity study with a 4-week recovery period in dogs, administration of S-637880-a compound that off-target inhibits steroid hormone synthesis in vitro-resulted in diffuse microvesicular vacuolation, which was considered to reflect excess lipid accumulation in adrenocortical cells. After the 4-week recovery period, these diffuse vacuolar lesions developed into characteristic multifocal macrovesicular vacuolation in the adrenal cortex, making it difficult to evaluate lesion reversibility. Immunohistochemical evaluation suggested that the histopathological changes observed after the recovery period reflected slow degeneration of lipid-laden adrenocortical cells, culminating in cell death accompanied by macrophage activation and aggregation to process apoptotic or necrotic cells and the liberated lipids. These findings are considered to represent a transitional phase in the recovery process. The reversibility of S-637880-induced vacuolar lesions was confirmed in a subsequent 13-week oral repeated-dose toxicity study with a 13-week recovery period. This case study may be helpful in evaluating the reversibility of vacuolar lesions in the adrenal cortex during nonclinical safety assessments and in determining an appropriate recovery periods for assessing adrenal toxicity.