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

MARTÍN, PL; CECCATTO, PAULA; RAZORI, MV; FRANCÉS, DEA; ARRIAGA SM; PISANI, GB; MARTÍNEZ, AI; SANCHEZ POZZI EJ; ROMA MG; BASIGLIO, CL

CLINICAL SCIENCE (LONDON, ENGLAND : 1979)

PORTLAND PRESS LTD

Lugar: Londres; Año: 2019 vol. 133 p. 117 - 134

0143-5221

We previously demonstrated in in vitro and ex vivo models that physiological concentrationsof unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanaliculardysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether asimilar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) inductionthat consequently elevates endogenous BR levels. This was achieved through the administrationof hemin, an inducer of HO-1, the rate-limiting step in BR generation. We foundthat BR peaked between 6 and 8 h after hemin administration. During this time period,HO-1 induction fully prevented the pro-oxidant tert-butylhydroperoxide (tBuOOH)-induceddrop in bile flow, and in the biliary excretion of bile salts and glutathione, the two maindriving forces of bile flow; this was associated with preservation of the membrane localizationof their respective canalicular transporters, bile salt export pump (Bsep) and multidrugresistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 inductioncounteracted the oxidation of intracellular proteins and membrane lipids induced bytBuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio,a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of theantioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented.We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thuspreventing consequent cholestasis. This reveals an important role for the induction of HO-1and the consequently elevated levels of BR in preserving biliary secretory function underOS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury thatbears an oxidative background.