Pro-oxidant properties of AZT and other thymidine analogues in macrophages: Implication of the azido moiety in oxidative stress

Zidovudine (azidothymidine, AZT) was the first drug approved for human immunodeficiency virus (HIV) treatment. Unfortunately, AZT is known to lead to severe side effects, many of which are generally thought to result from increased reactive oxygen species (ROS) production. In this work, the pro-oxidative properties of AZT and other thymidine analogues were investigated electrochemically at microelectrodes. Macrophages pre-incubated with AZT were found to release significant amounts of reactive species, including H ₂O₂, ONOO^-, NO^• and NO ₂ ^-. Interestingly, the total amounts of released species were the greatest when cells were incubated with azido-containing analogues. The pro-oxidative effect of these compounds decreased significantly when the free azide terminal group was modified by reaction with a triosmium cluster. As expected, thymidine incubation did not lead to any increase in overall ROS levels. This work implicates the azido moiety in AZT-induced oxidative stress.