allopurinol and Cholestasis--Intrahepatic

Cholestasis is one of the most severe manifestations of liver injury and has limited therapeutic options. Allopurinol (AP), an inhibitor of uric acid (UA) synthesis, was reported to prevent liver damage in several liver diseases. However, whether AP protects against intrahepatic cholestatic liver injury and what is the role of UA in the pathogenesis of cholestasis remain unknown. In this study, we reported that AP attenuated liver injury in a mouse model of intrahepatic cholestasis induced by alpha-naphthylisothiocyanate (ANIT). AP showed no significant effect on glutathione depletion, inflammation, or bile acid metabolism in livers of ANIT-treated mice. Instead, AP significantly improved fatty acid β-oxidation in livers of ANIT-treated mice, which was associated with activation of PPARα. The protective effect of AP on cholestatic liver injury was not attributable to the depletion of UA, because both exogenous and endogenous UA prevented liver injury in ANIT-treated mice via inhibition of NF-kB-mediated inflammation. In conclusion, the present study provides a new perspective for the therapeutic use of AP and the role of UA in cholestatic liver injury.

Topics: 1-Naphthylisothiocyanate; Allopurinol; Animals; Cholestasis; Cholestasis, Intrahepatic; Liver; Mice; Uric Acid

Basis on study through integrated comparative assessment of clinical, biochemical survey data revealed that in patients with impaired metabolism of uric acid in a greater percentage of common biliary sludge, a violation of the rheological properties of bile, a violation of cholate-cholesterol ratio index, which indicates an increased risk of bile stones. The study found that despite the high levels of uric acid there is a violation of the spectrum of bile acids, cholic and deoxycholic growth acid reduction taurocholic acid. Thus, application of ursodeoxycholic acid, rosuvastatin and allopurinol in these study patients with NAFLD dosages in combination with hyperuricemia improves the clinical symptoms and normalization of biochemical parameters and normalizes the spectrum of biliary acids.

Topics: Adult; Allopurinol; Bile; Cholagogues and Choleretics; Cholestasis, Intrahepatic; Cholesterol; Cholic Acid; Deoxycholic Acid; Drug Therapy, Combination; Duodenoscopy; Female; Fluorobenzenes; Humans; Hyperuricemia; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Taurocholic Acid; Uric Acid; Ursodeoxycholic Acid

Heme oxygenase (HO)-1 preconditioning through genetic or pharmacologic interventions was shown experimentally to improve posttransplant outcome of liver grafts. However, its clinical application requires careful consideration because of the complexity and economic costs of the procedures. This study aimed to examine if graft preconditioning with HO-1 could be substituted by a simple treatment with heme-degrading products such as bilirubin. Rats were pretreated with or without hemin, an HO-1 inducer for preconditioning. Their livers were harvested as grafts in University of Wisconsin (UW) solution for 16 hours at 4 degrees C and followed by reperfusion ex vivo or by transplantation in vivo. The control grafts were also treated with a rinse buffer containing varied concentrations of unconjugated bilirubin with different time intervals. The HO-1-preconditioned grafts ex vivo exhibited a marked improvement of bile output and cell injury that was cancelled by blocking HO with zinc protoporphyrin-IX. The aggravation of the graft viability by the inhibitor was repressed by supplementation of bilirubin but not by that of carbon monoxide. Furthermore, a short-term rinse treatment with micromolar levels of bilirubin attenuated biliary dysfunction and cell injury of the grafts both ex vivo and in vivo even without HO-1 preconditioning. The protective effects of HO-1 preconditioning or bilirubin rinse appeared to involve its inhibitory effects on lipid peroxidation in hepatocytes. In conclusion, these results suggest that bilirubin rinse serves as a simple strategy to ameliorate hyperacute oxidative stress and hepatobiliary dysfunction of the transplanted grafts, mimicking effects of HO-1-mediated preconditioning.

Topics: Adenosine; Allopurinol; Animals; Bile; Bilirubin; Carbon Monoxide; Cholestasis, Intrahepatic; Glutathione; Graft Survival; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hemin; Insulin; Ischemic Preconditioning; Liver Transplantation; Male; Organ Preservation Solutions; Oxidative Stress; Raffinose; Rats; Rats, Wistar; Reperfusion Injury