The role of oxygen metabolism for the pathological phenotype of Fanconi anemia

Human Genetics
Werner RuppitschMonica Hirsch-Kauffmann

Abstract

The molecular defect of the hereditary disease Fanconi anemia (FA) remains unknown. The two theoretical possibilities are (1) an impaired DNA crosslink-repair system or (2) a disturbed oxygen metabolism either by overproduction of reactive oxygen intermediates (ROI) or by diminished detoxification of ROI. In order to gain further insight into the molecular mechanism of this disease, we have determined the repair capacity of FA cells challenged by crosslinking agents and have analyzed diverse biological systems that are involved in oxygen metabolism. We have tested normal and FA cells for oxygen consumption and for the activity of the antioxidant phospholipid-hydroperoxide-glutathione-peroxidase (PHGPx). FA cells show a reduced oxygen consumption and an increased PHGPx activity. Since spontaneous and induced chromosomal instability is a main cellular feature of FA, we have analyzed the redox state of cells and the effect of cytochrome P-450 (Cyt P-450) inhibitors and inducers on chromosomal breaks and micronuclei production. Our results indicate that Cyt P-450 enzymes, especially Cyt P-450 1A2, play a crucial role in radical metabolism in FA cells. Furthermore, we have determined NF-kappa B activity in untransformed cells and in...Continue Reading

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