the current study, the effect of nilotinib, a marketed drug used by human beings that has a well-defined safety profile, was investigated on APAP-induced hepatotoxicity in mice. Nilotinib treatments for mice were found to protect against APAP-induced liver injury as indicated by decreasing the elevated levels of serum ALT, AST, LDH and GGT activities. The protective effect exerted by nilotinib against APAP-induced liver injury was further confirmed histopathologically by preventing APAP-induced necrosis in centrilobular areas of the liver.
An important mechanism for inhibiting APAP hepatotoxicity by nilotinib, especially at a dose of 25 mg/kg, was the stimulation of hepatic GSH synthesis and its related enzymes, which augmented the detoxification …show more content…
Moreover, the complete inhibition of hepatic MPO activity elevation by nilotinib treatments dose-dependently suggested that nilotinib prevented the accumulation of neutrophils that were generated in response to the inflammatory cytokines produced in APAP hepatotoxicity [35]. As a consequence of these potential mechanisms, nilotinib blunted APAP-induced oxidative stress and elevation of lipid peroxidation products, as demonstrated by hepatic MDA and 4-HNE …show more content…
Apart from ischaemia/reperfusion injury, JNK activation has an important role in mitochondrial dysfunction mediated by APAP overdosing [36]. The initial activator for JNK is the reactive oxygen species, which result from mitochondrial depletion of GSH in response to APAP overdosing [37]. Based on these findings, the beneficial effects exerted by nilotinib against APAP hepatotoxicity appear to be mediated by inhibiting the oxidative stress and subsequent JNK activation.
Some previous studies have reported that bcl-2 over-expression in hepatocytes protects against injury induced by hepatectomy [38], cholestasis [39], ischaemia/reperfusion [40] and Fas ligand [41]. Unexpectedly, bcl-2 overexpression has been shown to enhance APAP hepatotoxicity [42]. In harmony with this finding, nilotinib reduction in APAP hepatotoxicity might be linked to the inhibition of bcl-2 over-expression in the
An important mechanism for inhibiting APAP hepatotoxicity by nilotinib, especially at a dose of 25 mg/kg, was the stimulation of hepatic GSH synthesis and its related enzymes, which augmented the detoxification …show more content…
Moreover, the complete inhibition of hepatic MPO activity elevation by nilotinib treatments dose-dependently suggested that nilotinib prevented the accumulation of neutrophils that were generated in response to the inflammatory cytokines produced in APAP hepatotoxicity [35]. As a consequence of these potential mechanisms, nilotinib blunted APAP-induced oxidative stress and elevation of lipid peroxidation products, as demonstrated by hepatic MDA and 4-HNE …show more content…
Apart from ischaemia/reperfusion injury, JNK activation has an important role in mitochondrial dysfunction mediated by APAP overdosing [36]. The initial activator for JNK is the reactive oxygen species, which result from mitochondrial depletion of GSH in response to APAP overdosing [37]. Based on these findings, the beneficial effects exerted by nilotinib against APAP hepatotoxicity appear to be mediated by inhibiting the oxidative stress and subsequent JNK activation.
Some previous studies have reported that bcl-2 over-expression in hepatocytes protects against injury induced by hepatectomy [38], cholestasis [39], ischaemia/reperfusion [40] and Fas ligand [41]. Unexpectedly, bcl-2 overexpression has been shown to enhance APAP hepatotoxicity [42]. In harmony with this finding, nilotinib reduction in APAP hepatotoxicity might be linked to the inhibition of bcl-2 over-expression in the