Effects of arylacetamide deacetylase on ketoconazole-induced hepatotoxicity and adrenal dysfunction in mice

Abstract

Ketoconazole (KC) rarely induces liver injury and adrenal dysfunction when orally administered. In this study, the significance of arylacetamide deacetylase (Aadac)-mediated hydrolysis of KC on above toxicities was evaluated using Aadac knockout mice. In Aadac knockout mice, oral administration of KC diminished plasma corticosterone level, inducing inflammatory response and elevation of plasma ALT level, whereas such phenomena were not observed in wild-type mice. We found that Aadac deletion caused KC-induced liver injury via inhibition of glucocorticoid synthesis in adrenal gland.