Evidence of a systemic phenomenon for oxidative stress in cholestatic liver disease

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Abstract
BACKGROUND There is considerable evidence indicating that the severity of hepatic damage in individuals with cholestatic liver disease is causally associated with the extent of intrahepatic oxidative stress. Increased levels or accelerated generation of reactive oxygen species and toxic degradative products of lipid peroxidation have been reported in the plasma of individuals with chronic liver disease and animal models of liver disease. Hence, by virtue of their increased presence in the circulation, it is not unreasonable to suppose that they may account for extrahepatic tissue damage in chronic liver disease. MATERIALS AND METHODS This hypothesis was tested by determining plasma levels of the ubiquitous antioxidant glutathione (GSH) and lipid peroxides (LP), together with assessment of the extent of lipid peroxidation in the kidney, brain, and heart, in 24 day chronically bile duct ligated (CBDL) rats. The extent of lipid peroxidation in tissues was based on measurement of conjugated dienes, lipid peroxides, and malondialdehyde (MDA) content. Data were compared with identical data collected from unoperated control, pair fed, 24 day bile duct manipulated (sham operated), and pair fed sham operated rats. RESULTS In CBDL rats, total and reduced plasma GSH levels were almost half those determined in all control rats. Plasma, kidney, and heart LP levels were significantly increased in CBDL rats compared with controls. MDA levels were significantly higher in the kidney, brain, and heart homogenates prepared from CBDL rats compared with MDA content measured in tissue homogenates prepared from the four groups of control rats. CONCLUSIONS Our data show that experimental cholestatic liver disease is associated with increased lipid peroxidation in the kidney, brain, and heart. Hence we have concluded that the oxidative stress in cholestatic liver disease is a systemic phenomenon probably encompassing all tissues and organs, even those separated by the blood-brain barrier.