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Nilotinib Interferes with the Signalling Pathways Implicated in Acetaminophen Hepatotoxicity
Author(s) -
Shaker Mohamed E.
Publication year - 2014
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12144
Subject(s) - nilotinib , pharmacology , acetaminophen , medicine , glutathione , tyrosine kinase inhibitor , toxicity , tyrosine kinase , chemistry , receptor , enzyme , biochemistry , cancer
Nilotinib, a second‐generation tyrosine kinase inhibitor, has been recently approved for the treatment for chronic myeloid leukaemia. The objective of this study was to explore the potential effects of clinically relevant doses of nilotinib against acetaminophen ( APAP )‐induced hepatotoxicity in mice. To simulate the clinical application in human beings, nilotinib (25 and 50 mg/kg) was administered to mice 2 hr after APAP intoxication (500 mg/kg). The results indicated that nilotinib (25 mg/kg) (i) abolished APAP ‐induced liver injury and necro‐inflammation, (ii) increased hepatic‐reduced glutathione ( GSH ) and its related enzymes synthesis, (iii) suppressed hepatic oxidative/nitrosative stress cascades, (iv) decreased neutrophil accumulation in the liver, and (v) prevented the over‐expression of B‐cell lymphoma‐2 (bcl‐2), cyclin‐ D 1 and stem cell factor receptor (c‐ K it) proteins in the liver. Although nilotinib (50 mg/kg) acted through the same mechanisms, there was severe depletion in hepatic GSH content by nilotinib itself at that dose level, rather than the potent stimulation observed by using a dose of 25 mg/kg. Consequently, the mortality rate after 18 hr was 100% for nilotinib (50 mg/kg) + APAP (750 mg/kg) versus 60% for APAP (750 mg/kg) and 40% for nilotinib (25 mg/kg) + APAP (750 mg/kg) in the survival analysis experiment. In conclusion, nilotinib can counteract the hepatotoxicity produced by a non‐lethal dose of APAP . However, there is a risk of aggravating the mortality for a lethal dose of APAP when nilotinib is co‐administered at doses relatively high, or near to the clinical range because of hepatic GSH depletion and c‐kit inhibition.