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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 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.
AuthorsCristina Enriquez-Cortina, Maylin Almonte-Becerril, Denise Clavijo-Cornejo, Mayrel Palestino-Domínguez, Oscar Bello-Monroy, Natalia Nuño, Anayelly López, Leticia Bucio, Verónica Souza, Rogelio Hernández-Pando, Linda Muñoz, María Concepción Gutiérrez-Ruiz, Luis E Gómez-Quiroz
JournalToxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 135 Issue 1 Pg. 26-36 (Sep 2013) ISSN: 1096-0929 [Electronic] United States
PMID23764483 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antitubercular Agents
  • Reactive Oxygen Species
  • Hepatocyte Growth Factor
  • Alanine Transaminase
  • Isoniazid
  • Rifampin
Topics
  • Alanine Transaminase (metabolism)
  • Animals
  • Antitubercular Agents (toxicity)
  • Apoptosis (drug effects)
  • Chemical and Drug Induced Liver Injury (prevention & control)
  • Hepatocyte Growth Factor (pharmacology)
  • Isoniazid (toxicity)
  • Liver (metabolism, pathology)
  • Mice
  • Mice, Inbred BALB C
  • Oxidation-Reduction
  • Oxidative Stress (drug effects)
  • Reactive Oxygen Species (metabolism)
  • Rifampin (toxicity)

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