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A brief overview of mechanisms of mitochondrial toxicity from NRTIs
Author(s) -
Kohler James J.,
Lewis William
Publication year - 2007
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20223
Subject(s) - mitochondrial toxicity , mitochondrial dna , mitochondrion , biology , toxicity , zidovudine , in utero , virology , nucleoside analogue , immunology , medicine , genetics , pregnancy , human immunodeficiency virus (hiv) , nucleoside , fetus , viral disease , gene
Nucleoside reverse transcriptase inhibitors (NRTIs) in combinations with other antiretrovirals (highly active antiretroviral therapy, HAART) are the cornerstones of AIDS therapy, turning HIV infection into a manageable clinical entity. Despite the initial positive impact of NRTIs, therapeutic experience revealed serious side effects that appeared to originate in the mitochondria and which ultimately manifested as dysfunction of that organelle. It may be reasonable to consider that as the AIDS epidemic continues and as survival with HIV infection is prolonged by treatment with HAART, long‐term side effects of NRTIs may become increasingly common. This consideration may be underscored in children who are born to HIV‐infected mothers who received NRTI therapy in utero during gestation. The long‐term effect of that NRTI exposure in utero is not clear yet. This review examines some proposed mechanisms of NRTI mitochondrial toxicity, including genetic predisposition, defects in mitochondria DNA replication, the encompassing “DNA pol‐γ hypothesis,” the relationship between mitochondrial nucleotide and NRTI pools, mitochondrial DNA mutation and dysfunction, and oxidative stresses related to HIV infection and NRTIs. Mechanisms of mitochondrial toxicity are reviewed with respect to key cell biological, pathological, and pharmacological events. Environ. Mol. Mutagen., 2006. © 2006 Wiley‐Liss, Inc.