EXPERIMENTAL PROTOPORPHYRIA: EFFECT OF BILE ACIDS ON GRISEOFULVIN-INDUCED HEPATIC DAMAGE

Martinez, María. del Carmen., Batlle, Alcira & Afonso, Susana

Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP)- CONICET- University of Buenos Aires

We have previously reported that oral administration of Griseofulvin (Gris) (0.5% in the diet) produces a great redox imbalance in mice liver due to the accumulation of porphyrins, which are known to generate reactive oxygen species.

The major route of hydrophobic porphyrin elimination is their biliary excretion. Administration of Gris induces a reduction of bile flow parallel to an increase in hepatic porphyrin accumulation. It has been reported that protoporphyrin (PPIX) impairs the biliary secretion of phospholipids and cholesterol, but not that of bile acids. Since both PPIX and lipid secretion into bile are coupled processes, biliary excretion of porphyrins can also be  diminished.

Because alterations induced by Gris as a consequence of the high accumulation of porphyrins in liver were so important, they could not be reverted by traditional antioxidants such as a-tocopherol, b-carotene or ascorbic acid. So we decided to study the effect of some bile acids, such as deoxycholic acid (DXA), dehydrocholic acid, chenodeoxycolic acid, and ursodeoxycholic acid, which could accelerate the porphyrin excretion through the bile, in an attempt to diminish liver damage.

Administration of Gris alone induced in liver increased activity of Glutathione reductase (GRed) (144.60%), Superoxide dismutase (SOD) (167.93%), Alkaline phosphatase (Aph) (147.27%), g-GT (130.28%) and GST (133.28%); and high levels of total porphyrins (155.33%), glutathione (GSH) (142.39%), and P450 (130.86%).

DXA reduced the accumulation of porphyrins induced by Gris, and the hepatic levels of GSH were within control values, although GRed activity was still enhanced (150.59%). Also lipid peroxidation and the hepatic enzymes g-GT and Aph were about control values. The drug metabolizing system was not altered either when mice were fed with Gris plus DXA. These findings would indicate that the hepatic damage induced by Gris can be partially prevented by administration of DXA.