Modulation of Radiation-Induced Changes in the Xanthine Oxidoreductase System in the Livers of Mice by its Inhibitors

Abstract Srivastava, M., Chandra, D. and Kale, R. K. Modulation of Radiation-Induced Changes in the Xanthine Oxidoreductase System in the Livers of Mice by its Inhibitors. Radiat. Res. 157, 290 – 297 (2002). The xanthine oxidoreductase (XOD) system, which consists of xanthine dehydrogenase (XDH) and xanthine oxidase (XO), is one of the major sources of free radicals in biological systems. The XOD system is present predominantly in the normal tissues as XDH. In damaged tissues, XDH is converted into XO, the form that generates free radicals. Therefore, the XO form of the XOD system is expected to be found mainly in radiolytically damaged tissue. In this case, XO may catalyze the generation of free radicals and potentiate the effect of radiation. Inhibition of the XOD system is likely to attenuate the detrimental effects of ionizing radiation. We have examined this possibility using allopurinol and folic acid, which are known inhibitors of the XOD system. Swiss albino mice (7 – 8 weeks old) were given single doses of allopurinol and folic acid (12.5 – 50 mg/kg) intraperitoneally and irradiated with different doses of γ radiation at a dose rate of 0.023 Gy/s. The XO and XDH activities as well as peroxidative damage and lactate dehydrogenase (LDH) were determined in the liver. An enhancement of the activity of XO and a simultaneous decrease in the activity of XDH were observed at doses above 3 Gy. The decrease in the ratio XDH/XO and the unchanged total activity (XDH + XO) suggested the conversion of XDH into XO. The enhanced activity of XO may potentiate radiation damage. The increased levels of peroxidative damage and the specific activity of LDH in the livers of irradiated mice supported this possibility. Allopurinol and folic acid inhibited the activities of XDH and XO, decreased their ratio (XDH/XO), and lowered the levels of peroxidative damage and the specific activity of LDH. These results suggested that allopurinol and folic acid have the ability to inhibit the radiation-induced changes in the activities of XDH and XO and to attenuate the detrimental effect of this conversion, as is evident from the diminished levels of peroxidative damage and the decreased activity of LDH.

[1]  D,et al.  Lactic Dehydrogenase FLUORESCENCE SPECTRA OF TERNARY COMPLEXES OF LACTIC DEHYDROGENASE, REDUCED DIPHOSPHOPYRIDINE NUCLEOTIDE, AND CARBOXYLIC ACIDS* , 2003 .

[2]  R. Kale,et al.  Radiomodification of Xanthine Oxidoreductase System in the Liver of Mice by Phenylmethylsulfonyl Fluoride and Dithiothreitol , 2000, Radiation research.

[3]  R. Kale,et al.  Effect of radiation on the xanthine oxidoreductase system in the liver of mice. , 1999, Radiation research.

[4]  M. Benboubetra,et al.  Xanthine oxidase: four roles for the enzyme in rheumatoid pathology. , 1997, Biochemical Society transactions.

[5]  O. Saugstad,et al.  Role of xanthine oxidase and its inhibitor in hypoxia: reoxygenation injury. , 1996, Pediatrics.

[6]  V. Steele,et al.  Screening of potential chemopreventive agents using biochemical markers of carcinogenesis. , 1994, Cancer research.

[7]  T. Nishino.  The conversion of xanthine dehydrogenase to xanthine oxidase and the role of the enzyme in reperfusion injury. , 1994, Journal of biochemistry.

[8]  C. V. van Noorden,et al.  Conversion of xanthine dehydrogenase into xanthine oxidase in rat liver and plasma at the onset of reperfusion after ischemia , 1994, Hepatology.

[9]  B. Freeman,et al.  Xanthine oxidase activity in the circulation of rats following hemorrhagic shock. , 1993, Free radical biology & medicine.

[10]  R. Paroni,et al.  Effect of glutathione depletion on the conversion of xanthine dehydrogenase to oxidase in rat liver. , 1993, Biochemical pharmacology.

[11]  T. Yoshikawa,et al.  Role of oxygen-derived free radicals in inflammation. , 1993 .

[12]  F. Stirpe,et al.  Effects of hypoxia and ethanol on xanthine oxidase of isolated rat hepatocytes: conversion from D to O form and leakage from cells. , 1992, Chemico-biological interactions.

[13]  B B Fredholm,et al.  Neuroprotective role of adenosine in cerebral ischaemia. , 1992, Trends in pharmacological sciences.

[14]  M. Benboubetra,et al.  Localisation of xanthine oxidase to synovial endothelium. , 1991, Annals of the rheumatic diseases.

[15]  M. A. Rashid,et al.  Influence of allopurinol on cardiac complications in open heart operations. , 1991, The Annals of thoracic surgery.

[16]  H. Mohri,et al.  A clinical trial of allopurinol (Zyloric) for myocardial protection. , 1991, The Journal of thoracic and cardiovascular surgery.

[17]  J. Gollan,et al.  Enhanced activity of the free radical producing enzyme xanthine oxidase in hypoxic rat liver. Regulation and pathophysiologic significance. , 1991, The Journal of clinical investigation.

[18]  R. Ferrari,et al.  Role of oxygen free radicals in ischemic and reperfused myocardium. , 1991, The American journal of clinical nutrition.

[19]  R. Kale,et al.  Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. , 1990, International journal of radiation biology.

[20]  D. Granger,et al.  Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. , 1988, The American journal of physiology.

[21]  H. de Groot,et al.  Reoxygenation injury in isolated hepatocytes: cell death precedes conversion of xanthine dehydrogenase to xanthine oxidase. , 1988, Biochemical and biophysical research communications.

[22]  M. Höllwarth,et al.  Mechanisms of conversion of xanthine dehydrogenase to xanthine oxidase in ischemic rat liver and kidney. , 1988, The American journal of physiology.

[23]  C. V. Smith,et al.  Hypoxic damage generates reactive oxygen species in isolated perfused rat liver. , 1988, Biochemical and biophysical research communications.

[24]  P. Lajos,et al.  Post-anoxic hemodynamic performance. The effect of allopurinol and superoxide dismutase/catalase. , 1987, Transplantation Proceedings.

[25]  R. Simon,et al.  Plasma Xanthine Oxidase Activity in Patients With Adult Respiratory Distress Syndrome , 1987 .

[26]  T. Nishino,et al.  Interaction of milk xanthine oxidase with folic acid. Inhibition of milk xanthine oxidase by folic acid and separation of the enzyme into two fractions on Sepharose 4B/folate gel. , 1986, The Journal of biological chemistry.

[27]  D. Granger,et al.  Xanthine oxidase: biochemistry, distribution and physiology. , 1986, Acta physiologica Scandinavica. Supplementum.

[28]  M. Höllwarth,et al.  Ischemia-reperfusion injury: role of oxygen-derived free radicals. , 1986, Acta physiologica Scandinavica. Supplementum.

[29]  P. Manson,et al.  Effects of Superoxide Dismutase and Allopurinol on the Survival of Acute Island Skin Flaps , 1985, Annals of surgery.

[30]  S. Purcell,et al.  Inhibition of mammalian xanthine oxidase by folate compounds and amethopterin. , 1984, The Journal of biological chemistry.

[31]  P. Ward,et al.  Superoxide radical involvement in the pathogenesis of burn shock. , 1984, Circulatory shock.

[32]  Z. Kamiński,et al.  Intermediate dehydrogenase-oxidase form of xanthine oxidoreductase in rat liver. , 1979, The Biochemical journal.

[33]  I. Fridovich.  The biology of oxygen radicals. , 1978, Science.

[34]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[35]  G. Hitchings.  Pharmacology of allopurinol. , 1975, Arthritis and rheumatism.

[36]  R. Dewall,et al.  Effect of allopurinol in renal ischemia. , 1972, Surgery.

[37]  Jones Ce,et al.  Effect of allopurinol on hemorrhagic shock , 1969 .

[38]  J. Crowell,et al.  Effect of allopurinol on hemorrhagic shock. , 1969, The American journal of physiology.

[39]  R. Friedman,et al.  Augmentation of the incorporation of hypoxanthine into nucleic acids by the administration of an inhibitor of xanthine oxidase. , 1963, Biochimica et biophysica acta.