Hepatoprotective Effects of Suberoylanilide Hydroxamic Acid (A Histone Deacetylase Inhibitor) in Immunological Liver Injury in Rats

Abstract

One of the main reasons for the development of chronic liver disease is autoimmune hepatitis (AIH).  There is no clear etiological factor for AIH occurrence and no drug has been approved for its treatment. Vorinostat, a Histone deacetylase inhibitor (HDACi) has been shown to reduce inflammation. Our aim was to explore the therapeutic potential of vorinostat in a rat model of AIH induced by Concanavalin A (Con A). The rats were randomly divided into 4 groups; control group, con A (20 mg/kg/iv/wk) group, vorinostat (15 mg/kg/day p.o) group and Con A with vorinostat group. Blood and liver samples were collected at the end of the fourth and eighth weeks for biochemical and histopathological examinations. Results revealed that administration of Con A elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzymes, which were reduced to 52.8% and to 61.8% respectively on simultaneous administration of Vorinostat as compare to Con A group.  Furthermore, Vorinostat reduced fibrosis and diminished apoptosis as deduced by the decrease in the hepatic hydroxyproline content of the liver and tumor necrosis factor-alpha levels. Relative gene expression analysis of interleukin 1b and transforming growth factor beta were significantly decreased in groups treated with vorinostat. Histopathological analysis showed that administration of vorinostat significantly restored the well organized structure of the liver, decreased initial inflammation produced by Con A, reduced liver fibrosis and mitigated hepatic stellate cell’s activities. In conclusion, administration of vorinostat in Con A model of autoimmune hepatitis, significantly decreased liver inflammation and fibrosis. So vorinostat might show a novel therapeutic approach for management of autoimmune hepatitis and its obstacles.