A Difference in Internal Exposure Makes Newly Weaned Mice More Susceptible to the Hepatotoxicity of Retrorsine Than Adult Mice

Pyrrolizidine alkaloids (PAs) are known hepatotoxins. Children have been reported to be particularly susceptible to PA-induced hepatotoxicity. To improve our understanding of the mechanisms of the age-dependent difference in susceptibility to PA hepatotoxicity, a comparative study of hepatotoxicities of retrorsine (RTS), a representative PA, was performed in newly weaned (3-4 weeks of age) and adult mice (8-12 weeks of age). Intraperitoneal administration of RTS at a dose of 50 mg/kg induced limited increases in serum ALT and AST activities in adult mice, while the same dosage of RTS caused intensified increases in serum ALT and AST activities in newly weaned mice. Toxicokinetic and metabolic activation studies in vitro and in vivo were performed to examine the factors responsible for the observed difference in toxicity susceptibility in mice of both ages. The values of AUC(0-4h) in plasma and liver of newly weaned mice are higher (all by 1.4-fold) than those in adult mice given the same dosage of RTS. As expected, more plasma pyrrolic ester-glutathione (GSH) conjugates (1.3-fold more) and pyrrolic ester-derived hepatic protein adduction (1.3-fold more) were found in newly weaned mice. Administration of RTS induced dramatic decreases in hepatic GSH levels (as little as 55% remained) of newly weaned mice, while the same dose of RTS did not reveal such GSH depletion in adult mice. The V-max/K-m (CLint) for RTS metabolic activation in newly weaned mouse liver microsomes was found to be similar to that of adult mice. In conclusion, more internal exposure of RTS made newly weaned mice more susceptible to PA-induced hepatotoxicity.