Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat

We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous bilirubin (BR) levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6-8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert -butylhydroperoxide ( t BuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, Bsep and Mrp2, which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by t BuOOH, and fully prevented the increase of the oxidized-to-total glutathione ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the anti-oxidant enzymes catalase and superoxide dismutase were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an im...

Source: Clinical Science - December 11, 2018 Category: Biomedical Science Authors: Martin, P. L., Ceccatto, P. L., Razori, M. V., Frances, D. E., Arriaga, S. M., Pisani, G. B., Martinez, A. I., Sanchez Pozzi, E. J., Roma, M. G., Basiglio, C. L. Tags: PublishAheadOfPrint Source Type: research