Arylacetamide deacetylase knockout mice are sensitive to
ketoconazole-induced hepatotoxicity and adrenal dysfunction
Abstract
Background and Purpose Orally administered ketoconazole rarely induces
liver injury and adrenal dysfunction. In cellulo studies showed
that a metabolite formed by arylacetamide deacetylase (AADAC)-mediated
hydrolysis is relevant to ketoconazole-induced cytotoxicity. This study
tried to examine the significance of AADAC in ketoconazole-induced
toxicity in vivo using Aadac knockout mice. Experimental Approach
Wild-type and Aadac knockout mice orally received 150 or 300
mg/kg/day ketoconazole, and plasma parameters, the concentrations of
ketoconazole and N-deacetylketoconazole in plasma and tissues,
and hepatic mRNA levels of immune- and inflammatory-related factors were
measured. The effects of pretreatment with corticosterone (40 mg/kg,
s.c.) on ketoconazole-induced liver injury were also examined.
Key Results In a study of a single oral administration of 150 mg/kg
ketoconazole, the area under the plasma concentration curve values of
ketoconazole and N-deacetylketoconazole in Aadac knockout
mice were significantly higher and lower than those in wild-type mice,
respectively. With the administration of ketoconazole (300 mg/kg/day)
for 7 days, Aadac knockout mice showed higher mortality (100%)
than wild-type mice (42.9%), with significantly higher plasma alanine
transaminase and lower corticosterone levels, representing liver injury
and adrenal dysfunction, respectively. In Aadac knockout mice,
hepatic mRNA levels of immune- and inflammatory-related factors were
increased by the administration of ketoconazole, and the increase was
restored by the replenishment of corticosterone, which shows
anti-inflammatory effects. Conclusion and Implications Aadac
defects exacerbated ketoconazole-induced liver injury by inhibiting
glucocorticoid synthesis and enhancing the inflammatory response. This
in vivo study revealed that the hydrolysis of ketoconazole by
AADAC can mitigate ketoconazole-induced toxicities.