Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis

BASIGLIO, C.; TOLEDO, F; BOAGLIO A; ARRIAGA, SANDRA M.; OCHOA, EJ; SANCHEZ POZZI, ENRIQUE; MOTTINO, ALDO D; ROMA, MARCELO GABRIEL

ARCHIVES OF TOXICOLOGY.

SPRINGER

Lugar: Berlin; Año: 2014 vol. 88 p. 501 - 514

0340-5761

Abstract Bilirubin is an endogenous antioxidant withcytoprotective properties, and several studies highlight itspotential in the treatment of pro-oxidant diseases. We demonstratedthat oxidative stress (OS), a key feature in mosthepatopathies, induces cholestasis by actin cytoskeletondisarrangement and further endocytic internalization of keycanalicular transporters, such as the bile salt export pump(Bsep) and the multidrug resistance-associated protein 2(Mrp2). Here, we evaluated the capability of physiologicalconcentrations of unconjugated bilirubin (UB) to limit OSand the impairment in biliary secretory function inducedby the model pro-oxidant agent, tert-butylhydroperoxide(tBuOOH). UB fully prevented the formation of reactiveoxygen species and membrane lipid peroxidation inducedby tBuOOH in isolated rat hepatocytes. In the isolated rathepatocyte couplet model, UB (17.1 μM) prevented theendocytic internalization of Bsep and Mrp2 and the impairmentin their secretory function induced by tBuOOH.UB also prevented actin disarrangement, as evaluated byboth plasma membrane bleb formation and actin fluorescentstaining. Finally, UB prevented tBuOOH-inducedcPKC activation. Experiments in isolated perfused rat liversshowed that UB prevents the increase in oxidized glutathionebiliary excretion and the drop in bile flow and thebiliary excretion of specific Bsep and Mrp2 substrates