AZT induces oxidative damage to cardiac mitochondria: protective effect of vitamins C and E.
AZT (zidovudine) is a potent inhibitor of HIV replication and a major antiretroviral drug used for AIDS treatment. A major limitation in the use of AZT is the occurrence of severe side effects. The aim of this work was to test whether AZT causes oxidative damage to heart mitochondria and whether this can be prevented by supranutritional doses of antioxidant vitamins. An experimental animal model was used in which mice were treated with AZT for 35 days (10 mg/kg/day) in drinking water. Animals treated with antioxidant vitamins were fed the same diet as controls but supplemented with vitamins C (ascorbic acid, 10 g/ kg diet) and E (alpha-dl-tocopherol, 0.6 g/kg diet) for 65 days before sacrifice. This resulted in a daily intake of 1250 mg/kg/day (vitamin C) and 75 mg/kg/day (vitamin E). Cardiac mitochondrial DNA (mtDNA) of mice treated with AZT had over 120% more oxo-dG (8-oxo-7,8-dihydro-2'-deoxyguanosine, which is a biomarker of oxidative damage to DNA) in their mitochondrial DNA than untreated controls. AZT treatment also caused an increase in mitochondrial lipid peroxidation and an oxidation of mitochondrial glutathione. Dietary supplementation with supranutritional doses of the antioxidant vitamins C and E protected against these signs of mitochondrial oxidative stress. The oxidative effects of AZT are probably due to an increase in production of reactive oxygen species by mitochondria of AZT-treated animals, raising the possibility that oxidative stress may play an important role in the cardiotoxicity of AZT.
de la Asunción
José García
JG
Departament of Anesthesiology and Critical Care, University Clinical Hospital, Valencia, Spain.
Del Olmo
María L
ML
Gómez-Cambronero
Luis G
LG
Sastre
Juan
J
Pallardó
Federico V
FV
Viña
José
J
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001205:Ascorbic Acid / Q000627:therapeutic use*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000188:drug therapy*; D014810:Vitamin E / Q000627:therapeutic use*; D015215:Zidovudine / Q000009:adverse effects*
D004272:DNA, Mitochondrial; D014810:Vitamin E; D015215:Zidovudine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D005978:Glutathione; D001205:Ascorbic Acid