Cholestatic liver injury down-regulates hepatic glutathione synthesis.
Hepatocellular injury caused by cholestasis may be caused in part by oxidant stress. The purpose of this study was to establish how acute cholestasis might alter hepatic glutathione homeostasis and to determine whether injured hepatocytes are capable of reverting to normal glutathione homeostatic mechanisms. Acute cholestasis was achieved by surgical ligation of the common bile duct in rats. Bile duct ligation induced a 3.7-fold increase in hepatic glutathione content over 4 days. This increase was not due to increased hepatic activity of gamma-glutamylcysteine synthetase (GCS); on the contrary, whole-liver GCS activity was substantially diminished in the bile duct-ligated liver to 34 and 11% of normal after 4 and 7 days, respectively. To determine if hepatocytes removed from the cholestatic environment maintained these changes in glutathione homeostasis, hepatocytes were isolated from bile ductligated livers and established in primary culture. In cells isolated after 4 days of bile duct ligation, the elevated hepatocyte glutathione content decreased and the low GCS activity increased over 2 days in culture. More importantly, the ability of postcholestatic hepatocytes to substantially increase their glutathione synthetic capacity by increasing GCS activity in response to stress was preserved. This compensatory increase was due primarily to new protein synthesis. Together, these observations suggest that acute cholestasis impairs the ability of the liver to synthesize glutathione by down-regulating the key regulatory enzyme for its synthesis in response to acutely elevated glutathione levels and that the impaired glutathione synthetic capacity is corrected after cells are removed from the cholestatic environment.
Neuschwander-Tetri
B A
BA
Department of Internal Medicine, Saint Louis University of Medicine, St. Louis, MO 63110, USA.
Nicholson
C
C
Wells
L D
LD
Tracy
T F
TF
D000818:Animals; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000009:adverse effects / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D008298:Maleates; D005721:Glutamate-Cysteine Ligase; C014476:diethyl maleate; D005978:Glutathione