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Experimental cholestasis decreases concentration of the class alpha isoenzymes of glutathione S-transferase in rat liver cytosol

Cholestatic liver disease decreases the activity of a basic hepatic defensive enzyme, glutathione S-transferase (GST), but the underlying molecular mechanisms are poorly understood. Reduction of GST level in hepatocytes may have a major impact on the decreased activity of the enzyme in cholestasis. To test this hypotheses, we analyzed the enzymatic activity and concentration of the principal isoenzymes (class alpha and class mu) of hepatic GSTs during cholestasis induced by bile duct ligation (BDL) in rats. The total and specific class mu isoenzymes GST activities in the liver cytosol were measured colorimetrically, using as a substrates 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, respectively. The level of isoenzymes was estimated by measuring the concentration of different GST subunits separated by sodium dodecyl sulfate (SDS) electrophoresis. The total GST activity did not change during the first week and decreased about two-fold during the second week after BDL. The activity of the class mu isoenzymes increased during the first week and returned to the control level on Day 10 of cholestasis. On Days 3-14 after BDL, SDS electrophoresis revealed progressive reduction in the concentration of the Y a and Y c subunits comprising the class alpha isoenzymes of GST. The concentration of the Y b1 and/or Y b2 subunits comprising the class mu isoenzymes increased during the first week of cholestasis and returned to the control level thereafter. These results suggest that the reduction of total GST activity in the rat liver cytosol after BDL is caused by a selective depletion of the class alpha isoenzymes.