A study of the genotoxicity of tyrosine metabolites in rat primary hepatocytes

Abstract

Toxicity of tyrosine metabolite has been hypothesiszed, but not proven, to play a role in the ethiopathogenesis of hepatic alterations found in hereditary tyrosinemia type1 (HT1), a metabolic disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH). A deficiency of this enzyme results in liver failure, hepatocellular carcinoma (HCC) and renal tubular dysfunction. Two of tyrosine intermediate metabolites (pHPPA) and succinyl acetone (SA) were tested on the rat primary hepatocytes. DNA damage, DNA repair capacity and DNA methylation status of the liver cells treated with these two metabolites were measured. Comet assay was used to measure the DNA damage and the repair capacity, DNA methylation was measured with the cytosine extension assay. Experiments showed that pHPPA had impairment on the DNA repair capability of treated cells and also increased the absolute % unmethylated Sample revealing the hypomethylation potency of this metabolite. SA caused damage but the treated cells were able to repair the damage inflicted on them, the results showed no significant effect on the global DNA methylation status of these SA treated cells.