Abstract
The adrenal glands are the most sensitive target organ among the endocrine organs for compounds that have high fat solubility or that affect steroid hormone metabolism, since the adrenal cortex is particularly involved in the synthesis and secretion of various steroid hormones using cholesterol as a substrate. In the toxicity studies of these compounds, vacuolation and necrosis in the adrenal cortex are frequently observed. In our study, during a 4-week repeated-dose toxicity study in dogs, Compound X induced diffuse cortical vacuolation (lipidosis) accompanied by macroscopic adrenal enlargement and weight gain at the end of the administration period. After a 4-week recovery period, these lesions transitioned into cluster lesions consisting of cells with larger vacuoles in the middle cortical region of the adrenal. This made it difficult for us to determine the reversibility of vacuolation lesions in the adrenal cortex, although macroscopic enlargement and weight gain of the adrenal recovered. Therefore, in the subsequent 13-Week toxicity study in dogs, we set the recovery period to 12 weeks to confirm the reversibility of the vacuolation lesions mentioned above, and as a result, we were able to confirm the reduction in frequency and severity of the lesions after the recovery period. Prolonging the recovery period is useful for reliably confirming the reversibility of a lesion, but it is a trade-off with accelerating the drug development process. In this presentation, we would like to discuss how to interpret reversibility of vacuolation lesions in the adrenal cortex and the appropriate recovery period, considering the well-known information about adrenal gland’s physiological turnover and lipid metabolism and our experimental data about the above Compound X and Aminoglutethimide, which induce vacuolation in the adrenal cortex in animals.
