Several lines of evidence have suggested that hydroxyl radicals generated either by redox cycling a toxin utilizing endogenous enzymes, or as a result of metabolism which has been activated by a toxin, may be involved in the pathogenesis of neurodegenerative disorders. Hydroxyl radical damage may effect many different cell constituents. However, oxidative damage to neuronal DNA could result in impaired neuronal function if the damage remained unrepaired and accumulated. In order to measure DNA damage, either neuronal or mitochondrial, gas chromatographic-mass spectrometric methods are being developed for the detection of thymine glycol, one of the oxidation products of thymine. The method releases methyl 2-methylglycerate from double stranded DNA by several chemical steps, prior to derivatization for mass spectrometric detection. Results indicate that there is approximately one thymine glycol per million thymine molecules in undamaged DNA, and that more sensitive techniques are required in order to apply measurements to small quantities of DNA. However, excellent correlations have been observed in studies of the effects in vitro of crystalline silica on DNA strand breakage and thymine glycol production. In a separate collaborative study, the chemical structure of an endogenous benzodiazepine ligand is being determined by mass spectrometric techniques.
