title: Hepatocyte growth factor protects against isoniazid/rifampicin-induced oxidative liver damage.
abstract: 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 PKCδ 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.
authors.affiliation: Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, Mexico City, Mexico.
authors.forename: Cristina
authors.initials: C
authors.lastname: Enriquez-Cortina
authors.forename: Maylin
authors.initials: M
authors.lastname: Almonte-Becerril
authors.forename: Denise
authors.initials: D
authors.lastname: Clavijo-Cornejo
authors.forename: Mayrel
authors.initials: M
authors.lastname: Palestino-Domínguez
authors.forename: Oscar
authors.initials: O
authors.lastname: Bello-Monroy
authors.forename: Natalia
authors.initials: N
authors.lastname: Nuño
authors.forename: Anayelly
authors.initials: A
authors.lastname: López
authors.forename: Leticia
authors.initials: L
authors.lastname: Bucio
authors.forename: Verónica
authors.initials: V
authors.lastname: Souza
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernández-Pando
authors.forename: Linda
authors.initials: L
authors.lastname: Muñoz
authors.forename: María Concepción
authors.initials: MC
authors.lastname: Gutiérrez-Ruiz
authors.forename: Luis E
authors.initials: LE
authors.lastname: Gómez-Quiroz
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007538:Isoniazid / Q000633:toxicity*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012293:Rifampin / Q000633:toxicity*
chemical_list: D000995:Antitubercular Agents; D017382:Reactive Oxygen Species; D017228:Hepatocyte Growth Factor; D000410:Alanine Transaminase; D007538:Isoniazid; D012293:Rifampin
keywords: HGF; ROS.; c-Met; isoniazid; rifampicin