EFFECT OF POLYPHENOLS ANTIOXIDANTS ON A MOUSE MODEL OF PROTOPORPHYRIA

Martinez M.Del C., Afonso S.G., Batlle A.

 

CIPYP (CONICET-UBA), Buenos Aires, Argentina

 

 

Erythropoietic Protoporphyria (EPP) is an inherited disease biochemically characterized by protoporphyrin (PP) accumulation in bone marrow, erythrocytes, plasma, liver and faeces, due to a deficiency in ferrochelatase (FeChel). This mitochondrial enzyme is responsible for the insertion of ferrous iron in a molecule of PP to form haem. Hepatic clearance of PP through the biliary system can lead to precipitation of the highly hydrophobic porphyrin in biliary canaliculi, resulting in cholestasis, fibrosis and cirrhosis. Griseofulvin (Gris) is a widely used antimycotic. Besides its antifungal properties, it has many undesirable side effects. In laboratory animals, Gris can induce porphyrin accumulation and hepatocarcinogenesis. It has been shown that its porphyrinogenic action is due to the formation of N-methyl porphyrins, powerful inhibitors of FeChel. leading to the accumulation of the enzyme substrates, PP and Fe. The hepatic manifestations mimic those observed in EPP patients We have previously demonstrated the onset of oxidative stress in liver mice fed with variable concentrations of dietary Gris. Based in those observations, we have now studied the effect of several plant polyphenols on the oxidative stress induced by Gris in mice. Animals received ellagic acid (300 mg/l), quercetin (50 mg/l) or chlorogenic acid (50 mg/l) in drinking water, and simultaneously Gris (0.5%) in the diet. Control animals received standard diet for laboratory animals, and the corresponding controls for each polyphenol received standard diet plus the antioxidant in drinking water. ALA-S, GST and SOD activities, and liver porphyrins were elevated in all animals treated with Gris or Gris plus polyphenol (160%, 140%, 180% and 140%, respectively). Hepatic levels of GSH were only increased in mice treated with Gris or Gris plus quercetin (149% and 142%, respectively). Mitochondrial TBARS were slightly increased over the controls (129-133%) in animals receiving Gris plus antioxidant, while these levels were significantly increased (200%) in animals fed with Gris alone. Microsomal TBARS were increased only in animals receiving Gris alone (148%). Because FeChel is inhibited by Gris, hepatic porphyrin levels and ALA-S activity remain elevated. But polyphenols do protect the liver from lipid peroxidation induced by accumulated porphyrins. It is therefore expected that administration of biliary salts along with some of these polyphenols would increase clearance of hepatic porphyrins, so to improve the liver status of these animals.