Hemeoxygenase-1 inhibition induces a loss of antioxidant protection in rats with bile duct ligation.

TAURIZANO D.; MARTÍN P.L.; RAZORI M.V.; MASSA E.M.; PISANI G.B.; ARRIAGA S.M.; SÁNCHEZ POZZI E.J.; ROMA M.G.; BASIGLIO C.L.

Rosario, Santa Fe

Congreso; Reunión Anual de la Sociedad Argentina de Fisiología (SAFIS) 2019; 2019

Sociedad Argentina de Fisiología (SAFIS) 2019

We had demonstrated that hemeoxygenase 1 (HO1) induction, and consequently elevated bilirubin (BR), protects the liver from oxidative stress-induced cholestatic injury in vivo. To corroborate this protective role of BR, we evaluated the effect of HO1 inhibition on endogenous BR levels and BR antioxidant capacity in animals subjected to a cholestatic insult. Wistar rats were subjected to bile duct ligation (BDL, n=6) or sham surgery (Sh, n=5). HO1 was inhibited by Zn(II) protoporphyrin IX (PP, 30 mg/Kg b.w., i.p.) administered 24 h before BDL (PP+BDL, n=6) or Sh (n=5). Animals were euthanized 7 days after BDL. Blood samples were obtained before surgery (BS1) and before euthanasia (BS2) and BR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (gGT) and lipid peroxidation were determined. At euthanasia, liver samples were obtained for the assessment of lipid peroxidation. Results (media±SD for BS1/BS2 in Sh; BDL; PP+BDL) were, respectively: BR(mg/dL) 0.13±0.05/0.11±0.04; 0.35±0.02/8.60±0.15a; 0.13±0.01/0.50±0.08a,b. ALT(U/L) 48±7/39±3; 136±10/188±15a; 172±32/211±21a. AST(U/L) 131±38/136±22; 385±25/474±40a; 343±49/449±36a. ALP(U/L) 570±24/707±79; 343±1/1047±84a; 510±90/1015±120a. gGT(U/L) 0.2±0.1/0.3±0.1; 0.5±0.1/12.6±3.1a; 0.8±0.1/1.5±0.2a,b; (a)p<0.05 vs BS1 and Sh; (b)p<0.05 vs BDL. After 7 days of BDL, BR levels increased far more in BDL than in PP+BDL, corroborating the inhibition of HO1. Differences in ALT, AST, ALP and gGT were not significant between BDL and PP+BDL,evidencing the establishment of cholestasis in both groups. The increase in plasma lipid peroxidation (media ± SD) was higher in PP+BDL than in BDL (368±18% vs 177±10%, p<0.05), demonstrating that, under cholestatic conditions, oxidative damage worsens when BR production is impaired. Similar results were obtained for lipid peroxidation in liver tissue. We conclude that BR ameliorates oxidative damage induced by BDL, contributing to limit the progression of cholestatic diseases with oxidative background.