Effect of diethylmaleate on bile secretion and ultrastructural appearance of hepatocytes in normal rats and mutant rats with defective organic anion secretion


Service d'Hépatologie et INSERM U 24, Hôpital Beaujon, 100 Bd. du Général Leclerc, 92118 Clichy Cedex, France


Abstract: Diethylmaleate is an organic anion secreted into bile as a glutathione conjugate. Its transport by the hepatocyte is associated with dilatation of the Golgi apparatus and the appearance of small vesicles in the pericanalicular area. It has been speculated that the Golgi apparatus could play a role in the intracellular transport and/or the biliary canalicular secretion of diethylmaleate. The purpose of this work was to determine whether the alterations in the Golgi apparatus and the pericanalicular vesicles could mediate the canalicular secretion of diethylmaleate. Diethylmaleate biliary secretion and diethylmaleate-induced bile flow were measured in Sprague-Dawley rats, and in TR- rats which have an inherited defect in the excretion into bile of organic anions, including glutathione conjugates. Livers of both Sprague-Dawley and TR- rats were examined by electron microscopy, to characterize the changes in intracellular organelles. In Sprague-Dawley rats, as previously described, diethylmaleate administration was associated with an increase in bile flow, which was parallel in time to the secretion into bile of diethylmaleate conjugates. Electron microscopic examination of the liver after diethylmaleate administration showed dilatation of the Golgi saccules. In contrast, in TR- rats, the increase in bile flow and the secretion of diethylmaleate conjugates were nearly absent. Nevertheless, electron microscopic examination showed a dilatation of the Golgi saccules similar to that observed in Sprague-Dawley rats. TR- rats, in addition to the changes in the Golgi apparatus, had marked dilatation of the endoplasmic reticulum. These results show that biliary secretion of diethylmaleate conjugates was severely impaired in TR- rats, in spite of a dilatation of the Golgi apparatus and of the endoplasmic reticulum. We conclude that it is unlikely that the alterations in the Golgi apparatus (and the endoplasmic reticulum) induced by diethylmaleate play a role in the canalicular secretion of diethylmaleate. We do not exclude the possibility that these organelles could play a role in intracellular transport of this compound. Alternatively, these alterations could be due to a “toxic” effect of diethylmaleate accumulation in hepatocytes.