In vivo prooxidant state in Werner syndrome (WS): Results from three WS patients and two WS heterozygotes

PubMedID: 16036329The hypothesis was tested that Werner syndrome (WS) phenotype might be associated with an in vivo prooxidant state. A set of redox-related endpoints were measured in three WS patients, two of their parents, and 99 controls within a study of some cancer-prone and/or ageing-related genetic disorders. The following analytes were measured: (a) leukocyte 8-hydroxy-2'-deoxyguanosine; (b) glutathione from whole blood, and (c) plasma levels of glyoxal, methylglyoxal, 8-isoprostane, and some plasma antioxidants (uric acid, ascorbic acid, ?- and ?-tocopherol). Leukocyte 8-hydroxy-2'-deoxyguanosine levels showed a significant increase in the 3 WS patients vs. 85 controls (p < 10-7). The disulfide glutathione:glutahione ratio was significantly altered in WS patients (p = 0.005). Glyoxal and methylglyoxal levels were significantly increased (p = 0.018 and p = 0.007, respectively). The plasma levels of uric acid (p = 0.002) and ascorbic acid (p = 0.003) were also increased significantly in WS patients and in their parents. No significant alterations were found in the plasma levels of ?- and ?-tocopherol, nor of 8-isoprostane. This is the first report of in vivo alterations of oxidative stress parameters in WS patients. Further investigations on more extensive study populations are warranted to verify the relevance of an in vivo prooxidant state in WS patients. © 2005 Taylor & Francis Group Ltd.Universitat de València National Cancer Institute1Italian National Cancer Institute, I-80131 Naples, Italy, 2Department of Genetics, “Elena d’Aosta” Hospital, I-80136 Naples, Italy, 3Italian National Cancer Institute, IST I-16132 Genoa, Italy, 4Department of Organic Chemistry and Biochemistry, “Federico II” Naples University, I-80126 Naples, Italy, 5Division of Life Sciences, King’s College, London SE1 9NN, UK, 6Department of Physiology, University of Valencia, E-46010 Valencia, Spain, 7Department of Pediatrics, C¸ ukurova University, TK-01330 Adana, Turkey, 8Department of Metabolism and Pathologic Biochemistry, Istituto Superiore di Sanità, I-00161 Rome, Italy, and 9International Atomic Energy Agency-MEL, MC-98000 Principality of Monac

Fanconi anaemia proteins: major roles in cell protection against oxidative damage

Fanconi anaemia (FA) is a cancer-prone genetic disorder that is characterised by cytogenetic instability and redox abnormalities. Although rare subtypes of FA (B, D1 and D2) have been implicated in DNA repair through links with BRCA1 and BRCA2, such a role has yet to be demonstrated for gene products of the common subtypes. Instead, these products have been strongly implicated in xenobiotic metabolism and redox homeostasis through interactions of FANCC with cytochrome P-450 reductase and with glutathione S-transferase, and of FANCG with cytochrome P-450 2E1, as well as redox-dependent signalling through an interaction between FANCA and Akt kinase. We hypothesise that FA proteins act directly (via FANCC and FANCG) and indirectly (via FANCA, BRCA2 and FANCD2) with the machinery of cellular defence to modulate oxidative stress. The latter interactions may co-ordinate the link between the response to DNA damage and oxidative stress parameters (3, 6-12)