A brief overview of mechanisms of mitochondrial toxicity from NRTIs

Environmental and Molecular Mutagenesis - Tập 48 Số 3-4 - Trang 166-172 - 2007
James J. Kohler1, William Lewis2
1Department of Pathology, Emory University, Atlanta, Georgia
2Department of Pathology, Emory University School of Medicine, 101 Woodruff Circle, 7117 Woodruff Memorial Building, Atlanta, GA 30322, USA

Tóm tắt

Abstract

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.

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Tài liệu tham khảo

10.1136/sti.79.4.340

10.1016/0140-6736(91)91294-5

10.1016/S0733-8619(02)00019-1

10.1016/S0026-0495(00)80077-3

10.1042/bj1340707

10.1016/0022-510X(94)90034-5

10.1056/NEJM200207183470313

10.1016/S0021-9258(18)80156-9

Chen CH, 1991, Effect of anti‐human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity, Mol Pharmacol, 39, 625

10.1097/01.qai.0000131585.77530.64

Copeland WC, 1992, Human DNA polymerases α and β are able to incorporate anti‐HIV deoxynucleotides into DNA, J Biol Chem, 267, 21459, 10.1016/S0021-9258(19)36631-1

10.1056/NEJMoa012035

10.1086/375353

10.1056/NEJM199004193221602

10.1172/JCI1418

10.1073/pnas.031430998

10.1074/jbc.270.32.18929

10.1016/S0021-9258(18)41538-4

10.1073/pnas.90.16.7632

10.1016/S0021-9258(19)47098-1

10.1016/S0021-9258(19)68544-3

10.1073/pnas.83.21.8333

10.1093/nar/gkf392

10.1128/AAC.36.8.1688

Huang P, 1992, Selective action of 2′,3′‐didehydro‐2′,3′‐dideoxythymidine triphosphate on human immunodeficiency virus reverse transcriptase and human DNA polymerases, J Biol Chem, 267, 2817, 10.1016/S0021-9258(18)45952-2

10.1016/0006-291X(91)91884-F

10.1146/annurev.biochem.72.121801.161455

10.1016/S0149-2918(00)90004-3

10.1128/AAC.33.12.2109

Lamperth L, 1991, Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model, Lab Invest, 65, 742

10.1016/S0166-3542(03)00069-X

10.1038/nm0595-417

Lewis W, 1991, Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts, Lab Invest, 65, 228

10.1172/JCI115722

10.1021/bi00252a030

10.1161/01.RES.74.2.344

10.1038/labinvest.3780022

10.1038/labinvest.3780288

10.1038/labinvest.3780366

10.1038/nrd1201

10.1038/labinvest.3700301

Lewis W, Antiretroviral nucleosides, deoxynucleotide carrier, and mitochondrial DNA: Evidence supporting the DNA pol γ hypothesis, AIDS

10.1074/jbc.M101114200

10.1073/pnas.91.19.8731

10.1111/1469-7610.00737

10.1016/j.arr.2003.07.001

10.1016/S0887-8994(99)00117-4

10.1086/367849

10.1128/AAC.38.12.2743

10.1097/01.qai.0000137004.63376.27

10.1056/NEJM199510263331702

10.1073/pnas.82.20.7096

10.1126/science.1699273

10.1097/00126334-200309011-00013

10.1086/381449

Moraes CT, 1991, mtDNA depletion with variable tissue expression: A novel genetic abnormality in mitochondrial diseases, Am J Hum Genet, 48, 492

Nickel W, 1992, Interactions of azidothymidine triphosphate with the cellular DNA polymerases α, δ, and ϵ and with DNA primase, J Biol Chem, 267, 848, 10.1016/S0021-9258(18)48361-5

Nolan D, 2004, The role of nucleoside reverse transcriptase inhibitors in the fat redistribution syndrome, J HIV Ther, 9, 34

10.1128/AAC.47.11.3384-3392.2003

10.1016/0014-5793(94)00329-7

Parker WB, 1994, Mitochondrial toxicity of NRTI analogs, J NIH Res, 6, 57

10.1074/jbc.C200100200

10.1056/NEJM200207183470313

10.1111/j.1750-3639.1992.tb00682.x

10.1016/0921-8734(92)90018-K

10.1080/15216540500217735

10.2174/1568005054880163

10.1016/0006-2952(89)90245-1

10.1016/j.gene.2005.03.025

10.1002/ajmg.1379

10.1056/NEJM199510263331710

10.1016/S0891-5849(98)00199-3

10.1093/humrep/15.suppl_2.79

10.1093/nar/29.15.e74

10.1016/S1386-6532(03)00085-4

10.1073/pnas.63.3.871

10.1055/s-2007-1007160

10.1016/0003-9861(82)90519-7

10.1097/00042560-200202010-00002

10.1007/BF00763096

10.1126/science.283.5407.1482

10.1002/ajmg.1393

10.1016/0163-7258(90)90066-B

10.1046/j.1432-1033.2002.02954.x

10.1006/scdb.2001.0278

10.1097/00019052-200310000-00004

10.1006/geno.2000.6333