Abstract
Ischemia-reperfusion injury is related with oxygen free radicals; a reason which has been suggested for this is the conversion of xanthine dehydrogenase (XDH) into xanthine oxidase (XO). In the present study, metabolic control of the enzymic conversion by modulating the cellular redox potential was attempted. An amino acid, aspartate, was tested as a possible candidate on the assumption that as a participant in the malate/aspartate shuttle, it might modify the cellular NADH/NAD+ balance. Its effect was studied by measuring the level of lipid peroxidation as a thiobarbituric acid-reactive substance (TEARS) and the conversion ratio of XDH to XO in the perfused-rat livers. The experimental animals, male Sprague Dawley rats were divided into three groups: control, ischemia and ischemia/reoxygenation. To each group, aspartate was infused at 2 mM level. ischemia alone did not affect the level of TEARS or the conversion ratio of the enzyme, regardless of aspartate infusion. In contrast, reoxygenation of previously ischemia liver significantly elevated the level of TEARS and decreased the ratio of XDH to XO; both this level and this ratio were ameliorated by aspartate. The protective role of aspartate against oxidative stress induced by ischemia/reoxygenation can be explained by the fact that aspartate may correct the increased NADH/NAD ratio by facilitating NAD regeneration from NADH through the coupled aspartate aminotransferase/malate dehydrogenase reaction and the malate-aspartate shuttle. Aspartate application may thus contribute to the development of a preventive strategy against ischemia/reperfusion-induced oxidative damages.
Highlights
Ischemia/reperfusion injury is associated with the production of oxygen-derived free radicals inducing lipid peroxidation, which cause alterations in biomembraneassociated functions of the cell or subcellular organelles
The amount of thiobarbituric acid-reactive substance (TBARS) in the reoxygenation group in the absence of aspartate was 0.214 ± 0.003 nmol/mg protein, resulting in 25% increase compared to the control and ischemia
The amount of TBARS in this group was 0.180 ± 0.001 nmol/mg protein. These results indicate that aspartate may play a role in preventing ischemia/reperfusion injury by reducing the level of TBARS
Summary
Ischemia/reperfusion injury is associated with the production of oxygen-derived free radicals inducing lipid peroxidation, which cause alterations in biomembraneassociated functions of the cell or subcellular organelles. Ischemia/reperfusion-induced radical generation has been partially explained by the conversion of xanthine dehydrogenase (XDH) into xanthine oxidase (XO) (Parks et al, 1982; Roy and McCord, 1983). The ischemia causes the cellular increase of NADH, which has been shown to inhibit the activity of NAD+-dependent XDH (Ballard, 1971; Kato et al, 1990). The increased breakdown of ATP during ischemia aggravates accumulation of xanthines, requiring their metabolic conversion to uric acid by xanthine oxidase (Kamiike et al, 1982; Engerson et al, 1987)
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