The worldwide increment of multidrug- and
extensively drug-resistant tuberculosis has emphasized the importance of looking for new options in
therapeutics. Long-time usage or higher doses of
isoniazid and
rifampicin have been considered for the treatment of
multidrug-resistant tuberculosis; however, the risk of
liver failure is proportionally increased.
Hepatocyte growth factor (HGF) is a multitask
growth factor that stimulates both antiapoptotic and
antioxidant responses that counteract the toxic effects of
drug metabolism in the liver. The present work was focused to address the
antioxidant and antiapoptotic effects of HGF on
isoniazid- and
rifampicin-induced hepatotoxicity. BALB/c mice were subjected to
rifampicin (150mg/kg, intragavage [ig]) plus
isoniazid (75mg/kg, ig) for 7 days. Increments in
alanine aminotransferase activity, steatosis, apoptosis, and oxidative stress markers were found in animals. Recombinant HGF (iv) prevented all the harmful effects by increasing the activation of Erk1/2 and PKCĪ“ signaling pathways and
glutathione (GSH) synthesis. Furthermore, inhibition of endogenous HGF with anti-HGF antibody (iv) enhanced the
isoniazid- and
rifampicin-induced oxidative stress damage and decreased the GSH content, aggravating liver damage. In conclusion, HGF demonstrated to be a good protective factor against antituberculosis
drug-induced hepatotoxicity and could be considered a good adjuvant factor for the use of high doses of or the reintroduction of these antituberculosis drugs.