The effects of liver transplantation and cyclosporine on bile formation and lipid composition: an experimental study in the rat

doi:10.1016/0168-8278(88)80021-7

Journal of Hepatology

Volume 28, Issue 2, February 1998, Pages 329-336

https://doi.org/10.1016/0168-8278(88)80021-7 Get rights and content

Abstract

Background/Aims: Hepatic graft dysfunction is a major management problem in the early post-liver transplantation period. Our aims were to study how liver transplantation per se affects bile formation, and to investigate the role of cyclosporine in the pathogenesis of early graft dysfunction.

Methods: Syngeneic liver transplantation used male Lewis rats. Two weeks after transplantation, the rats were randomly assigned to receive either daily subcutaneous injections of cyclosporine 10 mg/kg for 1 week (n=8), or daily saline injections (Placebo, n=8). 24-h bile collections were performed 18 h after the last injection. Eight non-transplanted rats served as controls.

Results: Liver transplantation per se (Placebo) significantly increased basal bile flow (51%), particularly that portion which was bile salk-independent flow (81%), but did not impair bile kinetics or biliary lipid composition. Cyclosporine reduced basal bile flow and bile salt-independent flow by 41% and 30%, respectively. Bile salt synthesis was 52% suppressed, leading to a 22% decrease in the bile salt pool size. The recycling frequency of the bile salt pool was unaffected. The drug inhibited bile salt (37%) and phospholipid (23%) outputs; cholesterol secretion remained unaltered. This significantly elevated the cholesterol saturation of bile (25%).

Conclusions: Liver transplantation per se is choleretic and does not impair bile formation or lipid composition in this inbred rat model. Parenteral administration of high-dose cyclosporine induces cholestasis by inhibiting bile salt secretion and BSIF. Bile salt synthesis is down-regulated and the bile salt pool size decreased. The drug adversely affects biliary lipid composition by differential inhibition of bile salt and phospholipid outputs relative to an unchanged cholesterol secretion.

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We investigate the ability of S-adenosylmethionine (SAMe) to antagonize the cyclosporine A (CyA)-induced inhibition of biliary glutathione efflux induced by long-term administration of CyA (10 mg/kg per day-CyA₁₀ or 20 mg/kg per day-CyA₂₀ for 4 weeks) in rats. CyA treatment reduced the liver content of total glutathione and caused a significant increase in the oxidized-to-reduced glutathione ratio and the thiobarbituric acid-reactive substances (TBARS) concentration. When the rats were concurrently treated with SAMe (10 mg/kg twice daily) and CyA, all these parameters did not significantly differ from control values. Treatment with CyA induced a significant increase in liver GGT activity that was attenuated by coadministration of SAMe. Biliary efflux of total glutathione was significantly reduced in animals treated with CyA. These changes were abolished by SAMe administration. Following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates increased to a lesser extent in animals cotreated with SAMe when compared to those receiving only CyA. The significant decrease in biliary efflux of oxidized glutathione induced by CyA was totally (S+CyA₁₀) or partially (S+CyA₂₀) prevented by coadministration of SAMe. Our observations confirm that SAMe cotreatment in rats antagonizes CyA-induced inhibition in the biliary efflux of glutathione and suggest that protection against intrabiliary glutathione degradation plays a major role in this protective effect.
Effects of S-adenosylmethionine on intrabiliary glutathione degradation induced by long-term administration of cyclosporin A in the rat
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We investigate the ability of S-adenosylmethionine (SAMe) to antagonize the cyclosporine A (CyA)-induced inhibition of biliary glutathione efflux induced by long-term administration of CyA (10 mg/kg per day-CyA₁₀ or 20 mg/kg per day-CyA₂₀ for 4 weeks) in rats. CyA treatment reduced the liver content of total glutathione and caused a significant increase in the oxidized-to-reduced glutathione ratio and the thiobarbituric acid-reactive substances (TBARS) concentration. When the rats were concurrently treated with SAMe (10 mg/kg twice daily) and CyA, all these parameters did not significantly differ from control values. Treatment with CyA induced a significant increase in liver GGT activity that was attenuated by coadministration of SAMe. Biliary efflux of total glutathione was significantly reduced in animals treated with CyA. These changes were abolished by SAMe administration. Following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates increased to a lesser extent in animals cotreated with SAMe when compared to those receiving only CyA. The significant decrease in biliary efflux of oxidized glutathione induced by CyA was totally (S+CyA₁₀) or partially (S+CyA₂₀) prevented by coadministration of SAMe. Our observations confirm that SAMe cotreatment in rats antagonizes CyA-induced inhibition in the biliary efflux of glutathione and suggest that protection against intrabiliary glutathione degradation plays a major role in this protective effect.
Effects of aging and cyclosporin treatment on the hepatobiliary efflux of glutathione
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The aim of this study was to investigate the effects of cyclosporin (CyA) treatment on biliary glutathione efflux in rats of different ages (1, 2, 4, and 24 months). CyA treatment reduced the liver content of total glutathione in 1-, 2- and 24 month old rats (−30%, −43% and −30%, respectively). By contrast, oxidized glutathione (GSSG) concentration in liver tended to increase, although non significantly, in the rats aged 4 and 24 month (+36% and +28%, respectively). The oxidized-to-reduced glutathione ratio was significantly increased in 2-, 4- and 24 month old animals (+23%, +36% and >100%, respectively). Regarding biliary glutathione, our data indicate that efflux rates of total glutathione in control (untreated) rats increased to a maximum at 4 months, and decreased (−56%) in 24 month old rats, although values were still higher than those from young animals. CyA treatment significantly reduced biliary glutathione secretion except in 24 month old rats (−98%, −66% and −32%, at 1, 2 and 4 month, respectively). In addition, following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates into bile were significantly reduced by the drug only in 1- and 2 month old rats (−29% and −55%, respectively) and even tended to increase, although non significantly, in oldest animals. Our data indicate that inhibition of biliary glutathione efflux by CyA was greater in younger rats and support the view that increased intrabiliary catabolism of the tripeptide and inhibition of its canalicular transport could contribute to the decline in biliary glutathione secretion induced by the drug.
Effects of aging on the susceptibility to the toxic effects of cyclosporin A in rats. Changes in liver glutathione and antioxidant enzymes
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Free radicals are involved in aging and cyclosporin A-induced toxicity. The age-related changes in the liver oxidative status of glutathione, lipid peroxidation, and the activity of the enzymatic antioxidant defense system, as well as the influence of aging on the susceptibility to the hepatotoxic effects of cyclosporin (CyA) were investigated in rats of different ages (1, 2, 4, and 24 months). The hepatic content of reduced glutathione (GSH) increased with aging, peaked at 4 months, and decreased in senescent rats. By contrast, glutathione disulfide (GSSG) and thiobarbituric acid-reactive substances (TBARS) concentrations and superoxide dismutase, catalase, and glutathione peroxidase activities were higher in the oldest than in the youngest rats. CyA treatment, besides inducing the well-known cholestatic syndrome, increased liver GSSG and TBARS contents and the GSSG/GSH molar ratio, and altered the nonenzymatic and enzymatic antioxidant defense systems. The CyA-induced cholestasis and hepatic depletion of GSH, and the increases in the GSSG/GSH ratio, and in GSSG and TBARS concentrations were higher in the older than the mature rats. Moreover, superoxide dismutase and catalase activities were found to be significantly decreased only in treated senescent rats. The higher CyA-induced oxidative stress, lipoperoxidation, and decreases in the antioxidant defense systems in the aged animals render them more susceptible to the hepatotoxic effects of cyclosporin.

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The effects of liver transplantation and cyclosporine on bile formation and lipid composition: an experimental study in the rat

Abstract

Hepatology

Gastroenterology

Biochem Pharm

Gastroenterology

J Lipid Res

Gastroenterology

Gastroenterology

Characteristics of biliary lipid metabolism after liver transplantation

Hepatology

Bile composition and bile cast formation after transplantation of the liver in man

Transplantation

Bile compositional changes and cholesterol stone formation following orthotopic liver transplantation

Transplantation

Donor data in liver grafts with primary non-function - a preliminary analysis by the European Liver Registry

Transplant Proc

Increased incidence of cholelithiasis in heart transplant recipients receiving cyclosporine therapy

J Heart Transplant

Biliary secretion of bile acids, lipids, and bilirubin by the transplanted liver. A quantitative study in patients on cyclosporine

Transplantation

The bile acid independent flow is reduced in the transplanted liver

Transplant Int

Bile acid metabolism and biliary secretion in patients receiving orthotopic liver transplants: differing effects of cyclosporine and FK506

Hepatology

Animal models of hepatic allograft rejection

Semin Liver Dis

A surgical experience with 530 liver transplants in the rat

Surgery

Physiologic study of bile salt and lipid secretion in rats after transplantation

Ann Surg

Influence of liver transplantation and cyclosporine on bile secretion - an experimental study in the rat

Transplant Int

Cholestatic effect of cyclosporine in the rat. An inhibition of bile acid secretion

Transplantation

Inhibition of hepatocyte vesicular transport by cyclosporin A in the rat: relationship with cholestasis and hyperbilirubinemia

Hepatology