Study on the Lipid Composition of Rat Bile during Choleresis Induced by Diethyl Maleate

Abstract

Diethyl maleate (DEM) is known to produce a rapid depletion of hepatic glutathione (GSH) and to induce an immediate short-term choleresis in experimental animals. The aim of our investigation was to ascertain in rats the effect of DEM on biliary lipid composition during the increment in bile flow. Biochemical and morphological studies of liver tissue were conducted in parallel. In bile fistula rats, a doubling of bile flow occurred immediately after intraperitoneal injection of DEM (0.7 ml/kg body weight) returning to the basal level at 45 min. Choleresis diluted the total bile acid concentration, without modifying the secretion. The phospholipid concentration was not affected by DEM, resulting in increased output (p < 0.02 vs. controls). Both cholesterol concentration and output were significantly decreased during DEM-induced choleresis. These changes were promptly reversible together with the return of bile flow to control values. Biochemical determinations failed to show a DEM-induced modification of enzymatic activities of the microsomal drug biotransformation pathway. Instead, morphological studies revealed alterations of the Golgi apparatus in hepatocytes with marked distension of the cisternae in coincidence with choleresis. The results demonstrate that the bile acid-independent choleresis induced by DEM is accompanied by an alteration in biliary lipid secretion possibly related to an interaction of the drug with the cellular or subcellular membranes of hepatocytes.

Early Structural and Functional Changes in Liver of Rats Treated with a Single Dose of Valproic Acid

“…Until now, there are no reports of ultrastructural studies conducted in animal models. It is however well known that VPA is also a potent choleretic agent, inducing a dose-dependent increase in bile flow (7,8) and the drug could represent a useful tool in the study of subcellular events involved in bile production, as already shown with other hydrocholeretics (9,10).…”

Pharmacokinetic aspects of sulfobromophthalein transport after diethyl maleate pretreatment in rats

“…2). Diethyl maleate has been shown by different authors to react with glutathione in the presence of glutathione transferases, causing a depression of hepatic glutathione content for a period of 2 to 4 h (8,9,10,26). The diminished, capacity of the liver to transport the dye would result form the impairment in BSP conjugation and the subsequent reduction in the quantity of conjugated i.BSP available for excretion (Fig.…”

“…The most widely used depleting agent is diethyl maleate, a a,~-unsaturated compound introduced by Boyland & Chasseaud (7), which binds with glutathione and is excreted into bile, leading to a fall in the hepatic content of the tripeptide (8,9,10). This effect has made diethyl maleate a useful tool in detoxification and drug metabolism studies (11).…”