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

Cardiovascular Toxicology
I Tong MakWilliam B Weglicki

Abstract

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 microM) enhanced lipid peroxidation (TBARS formation) up to 51% above control. Significance (p < 0.05) was achieved by 6.7 microM 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 microM) promoted cell death further; at 20 microM 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 AZ...Continue Reading

Citations

Jul 5, 2006·Heart Failure Reviews·Maria Isabel Tejero-TaldoWilliam Bernard Weglicki
Jun 2, 2009·Cardiovascular Toxicology·I Tong MakWilliam B Weglicki
May 2, 2007·Antimicrobial Agents and Chemotherapy·Kaleb C LundKendall B Wallace
May 9, 2012·Free Radical Biology & Medicine·Kristi M Porter, Roy L Sutliff
Oct 31, 2020·Pathogens·Bikash Sahay, Ayalew Mergia

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