Induction of heme oxygenase-1 by hemin prevents oxidative stress-induced acute cholestasis in the rat

CECCATTO P.; ARRIAGA S.M.; MARTÍN P.L.; SÁNCHEZ POZZI E.J.; FRANCÉS D.; MARTINEZ A.; BASIGLIO C.L.; RAZORI M.V.; PISANI G.B.; ROMA M.G.

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 exvivo models that physiological concentrations of unconjugated bilirubin(BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction andcholestasis. Here, we aimed to ascertain, in the whole rat, whether a similarcholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction thatconsequently elevates endogenous BR levels. This was achieved through theadministration of hemin, an inducer of HO-1, the rate-limiting step in BRgeneration. We found that BR peaked between 6 and 8 h after heminadministration. During this time period, HO-1 induction fully prevented thepro-oxidant tert-butylhydroperoxide (tBuOOH)-induced drop in bileflow, and in the biliary excretion of bile salts and glutathione, the two main drivingforces of bile flow; this was associated with preservation of the membranelocalization of their respective canalicular transporters, bile salt exportpump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which areotherwise endocytosed by OS. HO-1 induction counteracted the oxidation ofintracellular proteins and membrane lipids induced by tBuOOH, and fullyprevented the increase in the oxidized-to-total glutathione (GSHt) ratio, asensitive parameter of hepatocellular OS. Compensatory elevations of theactivity of the antioxidant enzymes catalase (CAT) and superoxide dismutase(SOD) were also prevented. We conclude that in vivo HO-1 inductionprotects the liver from acute oxidative injury, thus preventing consequentcholestasis. This reveals an important role for the induction of HO-1 and theconsequently elevated levels of BR in preserving biliary secretory functionunder OS conditions, thus representing a novel therapeutic tool to limit thecholestatic injury that bears an oxidative background.