Secondary biliary cirrhosis in the rat is prevented by decreasing NF-κB nuclear translocation and TGF-β expression using allopurinol, an inhibitor of xanthine oxidase

Abstract

Allopurinol is an inhibitor of xanthine oxidase (XO), and XO is an enzyme that generates great amounts of reactive oxygen species. The aim of this work was to evaluate the efficacy of allopurinol to prevent experimental cirrhosis. Fibrosis and cirrhosis were induced by common bile duct ligation (BDL) for 4 weeks in rats. Animals were divided into 4 groups: sham-operated rats (SHAM); BDL group; BDL plus allopurinol (100 mg·kg⁻¹, p.o.), and SHAM plus allopurinol treatment. Alanine aminotransferase, γ-glutamyl transpeptidase, and alkaline phosphatase were increased in BDL rats but were preserved normal by allopurinol. XO activity was prevented by allopurinol; however, lipophilic and hydrophilic oxidative stress was not prevented by the drug. Allopurinol partially suppresses nuclear factor-κB (NF-κB) nuclear translocation and transforming growth factor-β (TGF-β) expression, and increased the active form of matrix metalloproteinase-13 (MMP-13). Moreover, collagen production induced by BDL was partially but significantly reduced by allopurinol. These findings suggest that allopurinol possesses a hepatoprotective effect probably by modulating proteins such as NF-κB, TGF-β, and MMP-13, helping to protect against liver damage induced by chronic cholestasis and a mechanism independent of oxidative stress.