Accumulation of DNA damage in the organs of mice deficient in gamma-glutamyltranspeptidase

We have used a differential alkaline single cell gel electrophoresis assay of DNA ("omet assay'' at pH 13 and 12.3) to evaluate DNA damage as a functi on of age in mice with an inherited defect in gluthathione (GSH) metabolism . The mice are homozygous null for gamma-glutamyltranspeptidase (GGT), the enzyme responsible for initiating the catabolism of GSH, and paradoxically have reduced levels of GSH and cysteine in many organs. We found an accumul ation of DNA damage in lung, liver and kidney in these mice as a function o f age. The largest differences were in assays run at pH 13, suggesting that the accumulation of apurinic/apryrimidinic (AP) sites and oxidative damage of DNA was largely responsible. In contrast, little if any accumulation of these lesions was detected in wild-type mice. Although these findings do n ot allow a precise analysis of the molecular basis of damage accumulation i n GGT-deficient mice, they implicate low GSH and cysteine levels as a cause of accumulative DNA. damage in the intact mammal. (C) 2000 Elsevier Scienc e B.V. All rights reserved.