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Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen‐induced liver injury
Author(s) -
Latchoumycandane Calivarathan,
Goh Catherine W.,
Ong Michie M.K.,
Boelsterli Urs A.
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21475
Subject(s) - leflunomide , pharmacology , acetaminophen , liver injury , mitochondrial permeability transition pore , chemistry , buthionine sulfoximine , apoptosis , programmed cell death , glutathione , medicine , biochemistry , immunology , enzyme , rheumatoid arthritis
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses but which can precipitate liver injury at high doses. We have previously found that the antirheumatic drug leflunomide is a potent inhibitor of APAP toxicity in cultured human hepatocytes, protecting them from mitochondria‐mediated cell death by inhibiting the mitochondrial permeability transition. The purpose of this study was to explore whether leflunomide protects against APAP hepatotoxicity in vivo and to define the molecular pathways of cytoprotection. Male C57BL/6 mice were treated with a hepatotoxic dose of APAP (750 mg/kg, ip) followed by a single injection of leflunomide (30 mg/kg, ip). Leflunomide (4 hours after APAP dose) afforded significant protection from liver necrosis as assessed by serum ALT activity and histopathology after 8 and 24 hours. The mechanism of protection by leflunomide was not through inhibition of cytochrome P450 (CYP)–catalyzed APAP bioactivation or an apparent suppression of the innate immune system. Instead, leflunomide inhibited APAP‐induced activation (phosphorylation) of c‐jun NH 2 ‐terminal protein kinase (JNK), thus preventing downstream Bcl‐2 and Bcl‐X L inactivation and protecting from mitochondrial permeabilization and cytochrome c release. Furthermore, leflunomide inhibited the APAP‐mediated increased expression of inducible nitric oxide synthase and prevented the formation of peroxynitrite, as judged from the absence of hepatic nitrotyrosine adducts. Even when given 8 hours after APAP dose, leflunomide still protected from massive liver necrosis. Conclusion: Leflunomide afforded protection against APAP‐induced hepatotoxicity in mice through inhibition of JNK‐mediated activation of mitochondrial permeabilization. (H EPATOLOGY 2007.)