Lamotrigine (LTG) has been widely prescribed as an
antipsychotic drug, although it causes idiosyncratic
drug-induced liver injury in humans. LTG is mainly metabolized by
UDP-glucuronosyltransferase, while LTG undergoes bioactivation by
cytochrome P450 to a reactive metabolite; it is subsequently conjugated with
glutathione, suggesting that reactive metabolite would be one of the causes for LTG-induced liver injury. However, there is little information regarding the mechanism of LTG-induced liver injury in both humans and rodents. In this study, we established an LTG-induced liver injury mouse model through co-administration with LTG and a
glutathione synthesis inhibitor, l-
buthionine-(S,R)-sulfoximine. We found an increase in
alanine aminotransferase (ALT) levels (>10 000 U/L) in C57BL/6J mice, with apparent interindividual differences. On the other hand, a drastic increase in ALT was not noted in BALB/c mice, suggesting that the initiation mechanism would be different between the two strains. To examine the cause of interindividual differences, C57BL/6J mice that were co-administered LTG and l-
buthionine-(S,R)-sulfoximine were categorized into three groups based on ALT values: no-responder (ALT <100 U/L), low-responder (100 U/L < ALT < 1000 U/L) and high-responder (ALT >1000 U/L). In the high-responder group, induction of hepatic oxidative stress,
inflammation and
damage-associated molecular pattern molecules in
mRNA was associated with vacuolation and karyorrhexis in hepatocytes. In conclusion, we demonstrated that LTG showed apparent strain and interindividual differences in liver
injuries from the aspects of initiation and exacerbation mechanisms. These results would support interpretation of the mechanism of LTG-induced liver injury observed in humans.