Abstract
Adrenal glands are one of endocrine glands which play a role in producing various hormones. Steroid hormones such as cortisol are mainly produced and secreted in zona fasciculata of cortex, they are synthesized from cholesterol. Intracellular cholesterol is transported to mitochondria by steroidogenic acute regulatory protein (StAR) and converted to hormones by metabolic enzymes such as CYP11A1 and HSD3B2. Therefore, exposure to compounds that affect the expression or function of StAR or metabolic enzymes cause cholesterol metabolism inhibition, resulting in adrenal toxicity.
Our candidate compounds caused adrenal toxicity in the cortex zona fasciculata (accumulation of lipid droplets) in non-clinical toxicity tests, suggested the inhibition of steroid hormone synthesis was occurred. For in vitro screening and mechanism exploring of this toxicity, we used H295R cells, a cell strain from human adrenal cortex and have ability to produce all major steroid hormones. As a result of verification using 20 in-house compounds, the plasma exposure and the degree of pathological adrenal findings in rats and the potential to inhibit cortisol synthesis in H295R cells showed a tendency to be related, suggesting the usefulness of H295R cells in evaluation for adrenocortical toxicity of our compounds.
We also explored the mechanism of adrenal toxicity caused by our compound using H295R cells. The results of experiment such as multiple analysis of steroid hormones and proteome analysis suggested that the compounds caused adrenal toxicity through inhibition of StAR function.
