Oxidative stress in NRTI-induced toxicity: evidence from clinical experience and experiments in vitro and in vivo.
This article reviews the relationship of oxidative stress with nucleoside reverse transcriptase inhibitor (NRTI)-induced toxicity and suggests how oxi-dative stress may participate in NRTI-mediated toxicity. NRTIs are pro-drugs that require intracellular phosphorylation to their 5' triphosphates by cellular kinases to inhibit viral and mitochondrial DNA (mtDNA) replication. NRTIs in highly active antiretroviral therapy have decreased morbidity and mortality, but side effects can be limiting after prolonged use. These side effects may be linked through mitochondrial dysfunction arising from altered mtDNA replication and oxidative stress via destruction of elements of mtDNA replication, decreased oxidative phosphorylation, and cellular function. Although oxidative stress is associated with NRTI therapy, there is still debate about whether it plays a direct role in NRTI-induced toxicity. The impact of oxidative stress on cardiovascular disease is likely to increase because patients with HIV infection are living longer as a result of effective antiretroviral therapy.
Department of Medicine, National Jewish Medical & ResearchCenter, Denver, CO 80206, USA. dayb@njc.org
Brian J
BJ
Day
William
W
Lewis
D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000378:metabolism; D002986:Clinical Trials as Topic; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D009705:Nucleosides / Q000009:adverse effects*; D018384:Oxidative Stress; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*
D004272:DNA, Mitochondrial; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors