Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues

Zhang, Yulin; Wang, Bishi; Liang, Qi; Qiao, Li; Xu, Bin; Zhang, Hongwei; Yang, Sufang; Guo, Hongbo; Wu, Jian; Chen, Dexi

doi:10.1007/s13365-015-0347-x

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…We argue that the actual mutagenic effect of lamivudine/adefovir is best reflected by the P gene because estimation bias is probably less pronounced than in the other genes, particularly S. Our analysis of the full set of SNPs revealed a specific enrichment in A/U→G/C substitutions in HBV sequences derived from treated patients. Recent work in mice chronically exposed to lamivudine has shown the same mutagenic pattern, as determined by sequence analysis of the highly variable D-loop region of mitochondrial DNA isolated from cortical neurons [ 52 ]. The fact that the mutational spectrum observed in treated patients was similar to that found in mouse mitochondrial DNA suggests a direct mutagenic effect of lamivudine/adefovir, as opposed to an alternative scenario in which HBV polymerase variants with modified mutational properties would have evolved in response to treatment.…”

Section: Discussionmentioning

confidence: 99%

Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients

et al. 2016

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The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10−5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses.

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Section: Discussionmentioning

confidence: 99%

Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients

et al. 2016

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“…mtDNA levels were also unaltered when analyzing the whole brain tissue, and changes were detected only when cortical neurons were isolated (Zhang et al 2014). These alterations were specifically identified as mutations of the mtDNA D-loop (Zhang et al 2015). Additionally, the Didanosine-induced decrease in mtCOXI expression observed in neurons was not found to be present in Schwann cells (Zhu et al 2007).…”

Section: Different Cells Different Vulnerabilitiesmentioning

confidence: 99%

Cerebral Vascular Toxicity of Antiretroviral Therapy

Bertrand

Velichkovska

Toborek

2019

J Neuroimmune Pharmacol

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HIV infection is associated with comorbidities that are likely to be driven not only by HIV itself, but also by the toxicity of longterm use of antiretroviral therapy (ART). Indeed, increasing evidence demonstrates that the antiretroviral drugs used for HIV treatment have toxic effects resulting in various cellular and tissue pathologies. The blood-brain barrier (BBB) is a modulated anatomophysiological interface which separates and controls substance exchange between the blood and the brain parenchyma; therefore, it is particularly exposed to ART-induced toxicity. Balancing the health risks and gains of ART has to be considered in order to maximize the positive effects of therapy. The current review discusses the cerebrovascular toxicity of ART, with the focus on mitochondrial dysfunction.

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“…Moreover, the structure character of the nucleotide analogue of guvermectin added causes worry about its safety to human beings and nontarget organisms, and how is its toxicity for its TPs in plants? Some short- or long-term mouse exposure experiments of nucleoside analogues had disclosed the adverse effects on mitochondrial toxicity, including increasing lactate production or mtDNA lesion in mouse hepatocytes. , Moreover, some toxicities to humans by nucleoside analogues, like lactic acidosis, myopathy, pancreatitis, and peripheral neuropathy, were also observed . Therefore, it is necessary to clarify the plant uptake and accumulation and toxicities of guvermectin and its metabolites before widespread commercial application.…”

Section: Introductionmentioning

confidence: 99%

Uptake and Biotransformation of Guvermectin in Three Crops after In Vivo and In Vitro Exposure

Shi,

Pan,

et al. 2024

J. Agric. Food Chem.

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Guvermectin, as a novel nucleoside-like biopesticide, could increase the rice yield excellently, but the potential environmental behaviors remain unclear, which pose potential health risks. Therefore, the uptake and biotransformation of guvermectin in three types of crops (rice, lettuce, and carrot) were first evaluated with a hydroponic system. Guvermectin could be rapidly absorbed and reached equilibrium in roots (12−36 h) and shoots (24−60 h) in three plants, and guvermectin was also vulnerable to dissipation in roots (t 1/2 1.02−3.65 h) and shoots (t 1/2 9.30−17.91 h). In addition, 8 phase I and 2 phase II metabolites, transformed from guvermectin degradation in vivo and in vitro exposure, were identified, and one was confirmed as psicofuranine, which had antibacterial and antitumor properties; other metabolites were nucleoside-like chemicals. Molecular simulation and quantitative polymerase chain reaction further demonstrated that guvermectin was metabolized by the catabolism pathway of an endogenous nucleotide. Guvermectin had similar metabolites in three plants, but the biotransformation ability had a strong species dependence. In addition, all the metabolites exhibit neglectable toxicities (bioconcentration factor <2000 L/kg b.w., LC 50,rat > 5000 mg/kg b.w.) by prediction. The study provided valuable evidence for the application of guvermectin and a better understanding of the biological behavior of nucleoside-like pesticides.

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Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues

Cited by 4 publications

References 39 publications

Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients

Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients

Cerebral Vascular Toxicity of Antiretroviral Therapy

Uptake and Biotransformation of Guvermectin in Three Crops after In Vivo and In Vitro Exposure

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