Difference in Internal Exposure Made New Weaned Mice More Susceptible to Hepatotoxicity of Retrorsine than Adult Mice

Drug‐induced liver injury (DILI) is an important and common hepatic disease. Pyrrolizidine alkaloids (PAs) containing plants are a common type of poisonous plants inducing DILI, due to their widespread prevalence and highly cytotoxic and genotoxic properties. It has already reported that young children appear to be particularly susceptible to PA‐induced liver injury. As a cutting point to gain the insight into the mechanisms of PA‐induced toxicities in infant animals, a comparative study on hepatotoxicities of retrorsine (RTS), a representative PA, was performed on new weaned (age of 3~4 week) and adult mice (age of 11~12 week). A single dose of RTS at 50 mg/kg (i.p.) induced minor increase in activities of serum ALT (312±115 U/L) and AST (246±60.9 U/L) in adult mice, while the same dosage of RTS caused intensified elevation of serum ALT (664±109 U/L) and AST (1055±340 U/L) in new weaned mice. Series of studies, including toxicokinetics and metabolism in vivo and in vitro , were carried out to explore the factors responsible for the observed difference in toxicity susceptibility in both ages of mice. The toxicokinetic study demonstrated that the absorption of RTS in new weaned mice was more efficient than that in adult mice. The values of AUC 0–8h in plasma and liver of infant mice are higher (1.36‐ and 1.5‐fold) than that in adult mice treated with same dosage of RTS. Accordingly, more plasma pyrrolic ester‐GSH conjugates (1.3‐fold) and pyrrolic ester‐derived hepatic protein adduction (1.3‐fold) were observed in infant mice than in adult ones at the first hour after given RTS. Treatment with RTS dramatically decreased hepatic GSH levels (as low as 55% remained) of new weaned mice, while no such GSH depletion was observed in adult mice. Enzyme kinetic study showed that the value of V max / K m ( CL int ) for RTS metabolic activation in new weaned mice liver microsomes (0.0139) was similar to that in adult mice (0.0143). The efficiencies of metabolic activation of RTS in liver microsomes of the two ages of mice were almost the same. In conclusion, more internal exposure of RTS in new weaned mice may be an important cause responsible for its high susceptibility to PA‐induced hepatotoxicity observed. Support or Funding Information Supported by Grant 81430086 and 81773813 (in part) of the National Natural Science Foundation of ChinaProposed pathway of pyrrolizidine alkaloid metabolic activationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .