Genetic risks of antiviral nucleoside analogues – a survey

Wutzler, Peter; Thust, R

doi:10.1016/s0166-3542(00)00139-x

Cited by 117 publications

(57 citation statements)

References 69 publications

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“…NRTI incorporation by X-and Y-family DNA polymerases would inhibit critical cellular pathways, such as base excision repair, nonhomologous end joining, translesion DNA synthesis, V(D)J recombination, and somatic hypermutation (18,29,43,55,58). Therefore, incorporation of a chain terminator at junctions with single-strand or double-strand DNA breaks would lead to genomic instability (21,37,57) and eventually trigger apoptosis in noninfected cells, which could lead to unwanted side effects (36). Besides NRTI incorporation by host enzymes, other processes can affect the efficacy and toxicity of the analog, such as drug uptake, transport, catabolism, and metabo- lism.…”

Section: Discussionmentioning

confidence: 99%

“…However, some drug toxicity occurs via Pol ␥-independent mechanisms (36, 52), such as the bone marrow toxicity associated with zidovudine (AZT) (2, 49) and the kidney toxicity associated with tenofovir (PMPA) (41,47). Another possible mechanism is analog incorporation into nuclear DNA (38, 49), since NRTIs induce genomic instability by increasing mutations, structural chromosomal aberrations, abnormal chromatin structure, sister chromatid exchanges, and shortened telomeres (36,37,57). Candidates responsible for NRTI insertion into nuclear DNA include three replicative, B-family DNA polymerases (Pols ␣, ␦, and ε) and the important base excision repair enzyme, Pol ␤ (an X-family member).…”

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confidence: 99%

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Pre-Steady-State Kinetic Analysis of the Incorporation of Anti-HIV Nucleotide Analogs Catalyzed by Human X- and Y-Family DNA Polymerases

Brown

Pack

Fowler

et al. 2011

Antimicrob Agents Chemother

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Nucleoside reverse transcriptase inhibitors (NRTIs) are an important class of antiviral drugs used to manage infections by human immunodeficiency virus, which causes AIDS. Unfortunately, these drugs cause unwanted side effects, and the molecular basis of NRTI toxicity is not fully understood. Putative routes of NRTI toxicity include the inhibition of human nuclear and mitochondrial DNA polymerases. A strong correlation between mitochondrial toxicity and NRTI incorporation catalyzed by human mitochondrial DNA polymerase has been established both in vitro and in vivo. However, it remains to be determined whether NRTIs are substrates for the recently discovered human X-and Y-family DNA polymerases, which participate in DNA repair and DNA lesion bypass in vivo. Using pre-steady-state kinetic techniques, we measured the substrate specificity constants for human DNA polymerases ␤, , , , , and Rev1 incorporating the active, 5-phosphorylated forms of tenofovir, lamivudine, emtricitabine, and zidovudine. For the six enzymes, all of the drug analogs were incorporated less efficiently (40-to >110,000-fold) than the corresponding natural nucleotides, usually due to a weaker binding affinity and a slower rate of incorporation for the incoming nucleotide analog. In general, the 5-triphosphate forms of lamivudine and zidovudine were better substrates than emtricitabine and tenofovir for the six human enzymes, although the substrate specificity profile depended on the DNA polymerase. Our kinetic results suggest NRTI insertion catalyzed by human X-and Y-family DNA polymerases is a potential mechanism of NRTI drug toxicity, and we have established a structure-function relationship for designing improved NRTIs.More than 30 million people worldwide are infected with the human immunodeficiency virus (HIV), which is the causative agent of AIDS. To manage the life-threatening effects of HIV replication, nucleoside reverse transcriptase inhibitors (NRTIs) have been a mainstay in effective combination antiretroviral therapy. NRTIs undergo phosphorylation by host cell kinases to be converted into their active di-or triphosphate (DP or TP) forms, which can serve as nucleotide substrates for HIV reverse transcriptase (RT). Incorporation of the NRTIs into the viral genome by HIV RT terminates the replication process due to the lack of a 3Ј-hydroxyl in these drugs. Unfortunately, host DNA polymerases (Pols), organized into the A, B, X, and Y families, are susceptible to drug inhibition, because these enzymes catalyze a nucleotidyl transfer reaction similar to that of HIV RT. Incorporation of the drug analog into human DNA will inhibit DNA replication and possibly lead to cell death and drug toxicity. A correlation has been established between the kinetics of nucleotide analog incorporation catalyzed by human DNA Pol ␥, an A-family member, and the observed clinical toxicity that presents as mitochondrial dysfunction (12,13,23,26). However, some drug toxicity occurs via Pol ␥-independent mechanisms (36, 52), such as the bone marrow toxicity as...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pre-Steady-State Kinetic Analysis of the Incorporation of Anti-HIV Nucleotide Analogs Catalyzed by Human X- and Y-Family DNA Polymerases

Brown

Pack

Fowler

et al. 2011

Antimicrob Agents Chemother

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“…Antiretroviral ilaçlar klinik olarak uzun süreli kullanılması gereken ilaçlar arasında yer aldığından, bu ilaçların çeşitli yan etkilerinin yanı sıra genotoksik ve kanserojenik potansiyellerinin de iyi bilinmesi gerekmektedir 9,10 . Bu çalışmada AIDS tedavisinde kullanılan antiretroviral ilaçlardan birisi olan tenofovir disoproksil fumaratın (TDF) insan lenfositlerinde genotoksik aktivitenin olup olmadığı kromozom aberasyon (KA), kardeş kromatid değişimi (KKD) ve mikronükleus (MN) testleri ile araştırılmıştır.…”

Section: Aidsunclassified

Evaluation of genotoxic activity of tenofovir disoproxil fumarate in human peripheral lymphocytes

Kurt¹,

Dönbak²,

Kayraldız³

2016

Cukurova Med J

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“…Nucleoside reverse transcriptase inhibitors are implicated as chemical mutagens and transplacental carcinogens [3,4,[8][9][10] and some consequences of DNA incorporation have been reported and categorized as gene mutations, chromosomal mutations, and telomere shortening [4].…”

Section: Azt Is Selectively Incorporated At the Telomeric Ends And Camentioning

confidence: 99%

Relevance of experimental models for investigation of genotoxicity induced by antiretroviral therapy during human pregnancy

Olivero

2008

Mutation Research/Reviews in Mutation Research

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The current incidence of HIV-1/AIDS affects around 7,000 pregnant women in the United States. When given during pregnancy, the nucleoside analog AZT significantly reduces maternal-fetal transmission. It has been previously shown that AZT is incorporated into DNA, where it causes mutations in the HPRT and TK genes. It also changes cell cycle gene expression, and induces S-phase arrest, micronuclei, chromosomal aberrations, sister chromatid exchanges, telomeric attrition, and other genotoxic effects in cultured cells. A predicted consequence of these events is genomic instability that together, with clastogenicity may contribute to the carcinogenic potency of AZT. Various aspects of genotoxicity are explored in this contribution seeking to understand the multiple effects of this antiretroviral agent in animal models and humans. This mini-review describes some of the experimental models used to elucidate the genotoxicity induced by antiretroviral therapy during human pregnancy. The use of diverse methods to detect biomarkers of exposure, such as an AZTspecific radioimmunoassay, micronuclei bearing intact chromosomes, and telomeric DNA attrition highlight the role of in-vitro models to elucidate exposure and risk. The relevance of the in vitro models is followed by the introduction of the role of the nucleoside analogs in transplacental carcinogenesis along with the description of a transplacental perfusion model and a transplacental carcinogenesis rodent model. In a more direct clinical application the use of AZT-DNA incorporation as a biomarker of exposure, in experiments conducted in vivo in Erythrocebus patas monkeys and in humans, addresses the possibility of elucidation of potential cancer risk in those infants exposed in utero.Two relevant aspects of this contribution are the potential application of some of the models described in this mini-review, as diagnostic tools in antiretroviral-exposed populations, and the use of these models to understand the nature of the genotoxicities and minimize the undesirable side effects of the antiretroviral therapy.

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Genetic risks of antiviral nucleoside analogues – a survey

Cited by 117 publications

References 69 publications

Pre-Steady-State Kinetic Analysis of the Incorporation of Anti-HIV Nucleotide Analogs Catalyzed by Human X- and Y-Family DNA Polymerases

Pre-Steady-State Kinetic Analysis of the Incorporation of Anti-HIV Nucleotide Analogs Catalyzed by Human X- and Y-Family DNA Polymerases

Evaluation of genotoxic activity of tenofovir disoproxil fumarate in human peripheral lymphocytes

Relevance of experimental models for investigation of genotoxicity induced by antiretroviral therapy during human pregnancy

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