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

CECCATTO, PAULA; ARRIAGA, SANDRA M.M.; SÁNCHEZ POZZI, ENRIQUE J.; RAZORI, MARÍA V.; PISANI, GERARDO B.; ROMA, MARCELO G.; MARTÍN, PAMELA L.; FRANCÉS, DANIEL E.A.; MARTÍNEZ, ALEJANDRA I.; BASIGLIO, CECILIA L.

CLINICAL SCIENCE (LONDON, ENGLAND : 1979)

PORTLAND PRESS LTD

Año: 2019 vol. 133 p. 117 - 134

0143-5221

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 important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background.