Changes in biliary secretion and lactate metabolism induced by diethyl maleate in rabbits

Diethyl maleate is a compound which binds with glutathione by means of a glutathione S-transferase and is excreted into bile leading to a rapid depletion of hepatic glutathione. In the rabbit, the activity of the enzyme is fairly low and we were thus prompted to study the possible effects of diethyl maleate on biliary secretion and metabolic status in this species. The administration of diethyl maleate induced a transient choleresis followed by cholestasis. The choleresis coursed with increases in the biliary output of sodium and unaccounted anions, whereas those of chloride, bicarbonate and bile acids were unaffected. Our data seem to confirm that choleresis is due to the osmotic activity of diethyl maleate compounds excreted into bile, as has been reported in rats and dogs. The cholestasis observed coursed with falls in the outputs of sodium, chloride and bicarbonate though that of bile acids remained constant. Following diethyl maleate administration, a metabolic acidosis appeared with progressive increases of blood lactate concentration. In bile the concentration of this anion closely followed that of plasma. The cholestasis is attributed to a lowered biliary secretion of bicarbonate probably secondary to the metabolic alteration. The hepatic values of cytoplasmatic and mitochondrial NADH/NAD ratios and of adenine nucleotide concentrations suggest that the increase in blood lactate results rather from a fall in its hepatic utilization that from an increase in its production.