Chemical SOD mimetics are not effective against steatohepatitis because they alter the antioxidant equilibrium inside the hepatocyte

Mitochondrial dysfunction and oxidative stress are critical players in the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). The mitochondrial respiratory chain, the major source of reactive oxygen species, is defective in patients with NASH. Superoxide dismutase (SOD) enzymes catalyze a reaction converting superoxide into oxygen and hydrogen peroxide. That is why chemical SOD mimetics have been developed and tested as therapeutic approaches against a wide range of diseases. Unfortunately combating NASH with such drugs is not possible.

A research conducted by Dr. José Carlos Fernández-Checa and his IDIBAPS team, Mitochondrial regulation of cell death and steatohepatitis, explains why in the Journal of Hepatology. Claudia von Montfort and Núria Matias, from the IIBB-CSIC-IDIBAPS, are the first authors of the study and was conducted in collaboration with investigators from CICBiogune in Bilbao and an international group of scientists from Los Angeles, Cambridge and Paris. According to the results, the administration of SOD mimetics alone worsens the progression of the disease because of an alteration of the delicate equilibrium between the antioxidant forces inside the cell.

The research was conducted in genetic and nutritional animal models of steatohepatitis. Both models showed an accelerated progression of the disease when treated with SOD mimetics alone. It may be due to an accumulation of hydrogen peroxide caused by the SOD mimetics, which could not be metabolized by the antioxidant enzymes of the mitochondria due to the intrinsic depletion of mitochondrial GSH. The IDIBAPS investigators managed to maintain the antioxidant equilibrium by administrating a permeable form of glutathione (GSH) together with the SOD mimetics. The additional GSH protected hepatocytes against the accumulation of hydrogen peroxide, which was reduced by enzymes such as GSH peroxidase 1 (GSHPx1). This discovery offers clues for the development of new therapies.

Due to the rising prevalence of obesity worldwide, NASH constitutes a global health concern urgently requiring more effective therapies. The present work shows that therapeutic approaches using antioxidant drugs must take into account the equilibrium between SOD and GSH enzymes. Dr. José Carlos Fernández-Checa is now involved in a one year stay at the University of Sourthern California (USC), in Los Angeles, to share knowledge about steatohepatitis and animal models. His future research, at the United States and back with his team at IDIBAPS, will keep focusing on the central role of mitochondria and the oxidative stress in steatohepatitis, and undertanding the mechanisms regulating the critical balance among antioxidant strategies for optimal defense.