High Concentrations of Excised Oxidative DNA Lesions in Human Cerebrospinal Fluid

The high rate of oxygen consumption per unit mass of tissue renders the brain especially vulnerable to the deleterious effects of oxidative stress, which can arise from the overproduction of reactive oxygen species or from a deficiency of the antioxidant defense systems. Reactive oxygen species have the potential to modify all four DNA bases. Production of 8-hydroxyguanine (8-OH-Gua) reflects one of the most critical lesions of this type (1)(2)(3).Products of DNA damage repair are excreted into the urine or other extracellular fluids without further metabolism (4)(5)(6). The rates of excretion of 8-OH-Gua and 8-hydroxy-2′-deoxyguanosine (8-OH-dGuo; modified base and nucleoside, respectively) in urine may be useful indicators of oxidative DNA damage and reflective of overall oxidative stress (6). It is also likely that the concentrations of modified base and nucleoside in urine reflect the activities of different repair pathways responsible for the removal of 8-OH-Gua from DNA, i.e., base excision repair and nucleotide excision repair (NER) (7)(8), which produce, respectively, 8-OH-Gua and 8-OH-dGuo. The analysis of 8-OH-Gua in body fluids presents particular difficulties (7)(9), but we have used HPLC followed by isotope-dilution gas chromatography–mass spectrometry to successfully measure 8-OH-dGuo and 8-OH-Gua in human urine (10)(11).Cerebrospinal fluid (CSF) filters and disposes of degraded cellular biomolecules from the brain. The concentrations of these modified base/nucleosides in CSF should therefore reflect the involvement of the repair processes in the central nervous system, whereas their excretion in urine should represent the same phenomenon in tissues/organs throughout the organism (7)(12).On the basis of experiments with cell culture, the hypothesis was put forward that, as opposed to other cell types, NER plays a major role in defending neurons from oxidative DNA damage (13). No in …