Pro-oxidant properties and cytotoxicity of AZT-monophosphate and AZT

被引：13

作者：

Mak I.T. ^{[1
,2
]}

Nedelec L.F. ^{[1
]}

Weglicki W.B. ^{[1
]}

机构：

[1] Division of Experimental Medicine, Dept. of Biochem. and Molec. Biology, George Washington Univ. Med. Center, Washington, DC

[2] Dept. of Biochem. and Molec. Biology, George Washington Univ. Med. Center, Ross Hall, Washington, DC 20037

来源：

Cardiovascular Toxicology | 2004年 / 4卷 / 2期

基金：

美国国家卫生研究院;

关键词：

AZT; AZT-MP; Cell viability; Endothelial glutathione; Iron and oxy-radicals; Membrane lipid peroxidation; Pro-oxidants;

D O I：

10.1385/CT:4:2:109

中图分类号：

学科分类号：

摘要：

The effects of zidovudine (AZT) and AZT-monophosphate (AZT-MP) on lipid peroxidation and oxidative cell injury were studied. When microsomal membranes from rat livers were peroxidized by a superoxide-driven, Fe-catalyzed oxy-radical system (ORS), both AZT-MP and, to a lesser extent AZT, but not thymidine, concentration dependently (2-100 μM) enhanced lipid peroxidation (TBARS formation) up to 51% above control. Significance (p < 0.05) was achieved by 6.7 μM AZT-MP. When cultured bovine aortic endothelial cells were incubated with the ORS for 60 min, total glutathione (GSH) decreased by 40% and 24-h cell survival, determined by the tetrazolium salt MTT assay, decreased by 38%. Using this cell system, AZT-MP (7-100 μM) promoted cell death further; at 20 μM 50% (p < 0.01), cell death was induced. In comparison, AZT was less effective. Concurrently, AZT-MP significantly promoted ORS-mediated loss of GSH. These cytotoxic effects were further exacerbated by low extracellular magnesium. Interestingly, when the endothelial cells were exposed to an iron-independent peroxynitrite generating system (SIN-1), the AZT-MP effects were absent. We propose that these pro-oxidant properties of AZT-MP are iron dependent. Because AZT-MP is a major phosphorylated metabolite, the data suggest that potential pro-oxidative activities may be associated with AZT use when catalytic iron is present.

引用

页码：109 / 115

页数：6

共 23 条

[1]

Lewis W., Day B.J., Copeland W.C., Mitochondrial toxicity of NRTI antiviral drugs: An integrated cellular perspective, Nat. Rev. Drug Discov., 2, pp. 812-822, (2003)

[2]

Lewis W., Copeland W.C., Day B.J., DNA depletion, oxidative stress and mutation: Mechanisms of dysfunction from NRTIs, Lab. Invest., 81, pp. 777-790, (1998)

[3]

Staal E.J., Glutathione and HIV infection: Reduced reduced, or increased oxidized?, Eur. J. Clin. Invest., 28, pp. 194-196, (1998)

[4]

Aukrust P., Muller F., Svardal A.M., Ueland T., Berge R.K., Froland S.S., Disturbed glutathione metabolism and decreased antioxidant levels in HIV-infected patients during highly active antiretroviral therapy-potential immunomodulatory effects of antioxidants, J. Infect. Dis., 188, pp. 232-238, (2003)

[5]

De La Asunciion J.G., Del Olmo M.L., Sastre J., Pallardo F.V., Vina J., AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins, J. Clin. Invest., 102, pp. 4-9, (1998)

[6]

Papadopulos-Eleopulos E., Turner V.F., Papadimitriou J.M., Causer D., Alphonso H., Miller T., A critical analysis of the pharmacology of AZT and its use in AIDS, Curr. Med. Res. Opin., 15, (1999)

[7]

Barry M.G., Khoo S.H., Veal G.J., Et al., The effect of zidovudine dose on the formation of intracellular phosphorylated metabolites, AIDS, 10, pp. 1361-1367, (1996)

[8]

Veal G.J., Back D.J., Metabolism of zidovudine, Gen. Pharmacol., 26, pp. 1469-1475, (1995)

[9]

Mak I.T., Murphy A.M., Hopper A., Witiak D., Ziemniak J., Weglicki W.B., Potent inhibitory activities of hydrophobic aci-reductones against membrane and human LDL oxidation, Biochem. Pharmacol., 55, pp. 1921-1926, (1998)

[10]

Mak I.T., Zhang J., Weglicki W.B., Cytoprotective properties of nisoldipine and amlodipine against oxidative endothelial cell injury, Ann. NY Acad. Sci., 899, pp. 399-402, (2000)

← 1 2 3 →