Carbon tetrachloride‐induced hepatotoxicity in weaning and adult mice

Abstract

Age‐related differences in drug‐induced liver injury (DILI) have been reported, but DILI in children has been not fully understood as compared to that in adults. In the present study, male ICR mice at two different ages, 2 (weaning) and 8 (adult) week‐old, were intraperitoneally injected with CCl4 (15.4 mg/kg), and the time‐dependent liver damage and cellular events were compared. Significant elevation of serum ALT/AST levels and hepatic centrilobular necrosis were induced by CCl4 in weaning mice, while mild liver injury was observed in adult mice. CCl4‐treated weaning mice showed higher pro‐apoptotic proteins (Bax, cleaved caspase‐3, ‐7, and ‐9), activated MAPKs (p‐JNK and p‐Erk), and ER stress indicators (ATF6 and CHOP), but lower anti‐apoptotic Bcl‐2 in their livers than those in the adult mouse livers. Weaning mice showed higher basal level of hepatic GSH due to their higher GCL and lower CDO enzyme levels. However, after CCl4 injection, hepatic GSH in weaning mice was dramatically decreased, while that in adult mice was not changed. Hepatic malondialdehyde, 4‐hydroxynonenal, nitrotyrosine‐protein adducts, and oxidized proteins resulting from oxidative stress were highly detected in CCl4‐administered weaning mice compared to the corresponding adult mice. The higher levels of CYP2E1 and 3A in the weaning mouse livers appear to be the primary reason of their higher hepatic susceptibility, and the lower GST‐π and GR in these mice also could contribute to the liver damage.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (NRF‐2018M3A7B4071233 and NRF‐2019R1I1A3A01058584).