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    Determining DNA damage and repair in human cells exposed to metabolites characteristic for tyrosinemia

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    Date
    2005
    Author
    Van Dyk, Etresia
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    Abstract
    Hereditary Tyrosinemia (HTI) is an autosomal recessive disorder caused by a deficiency of fumarylacetoacetate hydrolase (FAH) but the mechanism by which the hepatic and renal symptoms of HTI arise is largely unknown. The current hypothesis is that the final metabolites of tyrosine catabolism (maleylacetoacetate and fumarylacetoacetate, and their derivatives, succinylacetone and succinylacetoacetate) are toxic, and can possibly act as alkylating agents and/or disrupt sulfhydryl metabolism. In addition, aminolevulinic acid (ALA) accumulates under pathological conditions. Development of hepatic tumours is a characteristic of this inherited disease. The aim of this study was to use the comet assay (single cell gel electrophoresis) with isolated lymphocytes and primary hepatic cells to study the genotoxicity of the accumulating metabolites to contribute towards a better understanding of the underlying mechanisms responsible for the pathophysiology of this disease. From the results it was seen that the exposure of both isolated lymphocytes and hepatocytes to SA, ALA and pHPPA separately, caused DNA damage but a high degree of DNA repair in the exposed cells was also observed. Upon further investigation it was seen that the damage caused by SA and ALA inhibited the cells' capacity to repair damaged DNA but some repair was still possible as was reflected in the low calculated repair capacity. The marked increase in DNA damage in isolated lymphocytes and the much lower calculated repair capacity in the hepatocytes, however, suggested that specific damage caused by pHPPA may have had an effect on the repair mechanisms of the cell. Contrary to previous reports (Mitchell et a/, 2001), pHPPA could have a definitive role in contributing to the clinical features such as the hepatocarcinogenesis characteristic of HT1.
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    http://hdl.handle.net/10394/868
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    • Natural and Agricultural Sciences [1730]

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