Isoniazid-induced liver injury and immune response in mice

Abstract

Isoniazid (INH) is associated with one of the highest incidences of idiosyncratic drug-induced liver failure of any commonly prescribed drug. The mechanism of this liver injury remains uncertain, and a valid animal model would greatly facilitate mechanistic studies. Most studies of INH-induced liver toxicity have been acute studies performed in rats with high doses of the drug, and this is very different from the idiosyncratic liver injury that occurs in humans. It has previously been demonstrated that covalent binding of INH in the liver of mice is greater than in rats and more like that in humans. Therefore, mice should be a better species in which to develop an animal model of INH-induced liver injury. Treatment of Cbl-b^−/− and PD1^−/− mice, which have impaired immune tolerance, resulted in greater injury than their C57BL/6 background, but not liver failure. This suggested that the injury was mediated by the adaptive immune system; however, Rag^−/− mice, which do not have competent T- and B-cells, sustained more liver injury than C57BL/6 wild-type mice. This suggested that the adaptive immune system also played a protective role. INH treatment also led to a decrease in the inflammatory cytokines IL-1α and IL-12, which suggests that the drug may have immunosuppressive properties. In short, a mouse model was developed of INH-induced liver injury in which the immune system appears to play a both protective and pathogenic role, but this study was unable to develop a model of INH-induced liver failure.

• Animal model
• drug-induced liver injury
• idiosyncratic adverse drug reaction
• immunosuppression
• tolerance

Acknowledgements

Jack Uetrecht holds the Canada Research Chair in Adverse Drug Reactions. Imir G. Metushi is a trainee of the Drug Safety and Effectiveness Cross Disciplinary Training Program that is funded by the Canadian Institutes for Health Research. The Canadian Institutes for Health Research also supplied operating funds for this research. We would like to thank Dr Pamela Ohashi for giving us breeding pairs of PD1^−/− and Cbl^−/− mice, as well as for providing us with anti-CD4/CD8 antibody. We thank Dr Tony Hayes for interpretation of the liver H&E slides.