Longitudinal effects of thymidine analogues on mtDNA, mtRNA and multidrug resistance (MDR-1) induction in cultured cells

Papp, Eszter; Gadawski, Izabella; Côté, Hélène

doi:10.1093/jac/dkn067

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…However, in this study, ABC did not affect mtDNA consistently or in a manner that correlated with the cytotoxicity observed. Increases in mtDNA following exposure to NRTIs have been noted both in vitro and in vivo and may be an initial response to cytotoxic stress (31,32). ABC is a guanosine analog and has not been shown to inhibit mtDNA polymerase ␥ in vitro (33,34), indicating that the cytotoxicity observed was most likely related to some other mechanism than impairment of mtDNA replication by ABC.…”

Section: Discussionmentioning

confidence: 99%

BMS-986001, an HIV Nucleoside Reverse Transcriptase Inhibitor, Does Not Degrade Mitochondrial DNA in Long-Term Primary Cultures of Cells Isolated from Human Kidney, Muscle, and Adipose Tissue

Wang¹,

Flint²

2013

Antimicrob Agents Chemother

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Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remain the cornerstone of HIV treatment; however, they are associated with toxicities attributed in part to inhibition of mitochondrial DNA (mtDNA) polymerase ␥. In this study, we compared the in vitro toxicity profiles of structurally similar NRTIs (BMS-986001 to stavudine and tenofovir to adefovir) that differ by the presence of an acetylene or methyl group, respectively. Primary cultures of human renal proximal tubule epithelium, skeletal muscle myotubes, and differentiated adipocytes were exposed to the NRTIs at the maximum concentration (C max ) reported for the clinically approved dose (investigational dose for BMS-986001, 600 mg) and a high equimolar concentration (200 M) for 19 days. After 19 days, BMS-986001 did not significantly decrease mtDNA or cell protein at either concentration in any cell line. In contrast, stavudine significantly decreased mtDNA in all cultures (1.5-to 2.5-fold) (except at C max in renal cells) and cell protein in renal cells (1.4-to 2.4-fold). By day 19, at 200 M, tenofovir significantly reduced mtDNA in adipocytes (1.9-fold) and adefovir significantly decreased mtDNA in all cultures (3.7-to 10.2-fold); however, no significant reduction in mtDNA was observed at C max in any cell line. Adefovir also significantly reduced cell protein at both concentrations in renal cells (2.2-to 2.8-fold) and at 200 M in muscle cells (2.0-fold). In conclusion, BMS-986001 and tenofovir were considerably less cytotoxic than their respective structural analogs, demonstrating that small structural differences can contribute to significant differences in toxicity.

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Section: Discussionmentioning

confidence: 99%

BMS-986001, an HIV Nucleoside Reverse Transcriptase Inhibitor, Does Not Degrade Mitochondrial DNA in Long-Term Primary Cultures of Cells Isolated from Human Kidney, Muscle, and Adipose Tissue

Wang¹,

Flint²

2013

Antimicrob Agents Chemother

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“…It is an analogue of thymidine that has been associated with mitochondrial dysfunction and haematological toxicity, including neutropenia and severe anaemia, and so may not be suitable for treatment of MMA patients. Zidovudine has been previously found to cause a transient increase in mitochondrial DNA in cultured cells, with a subsequent increase in mRNA levels [21,22]. We have shown that gene expression from genomic DNA can also be increased transiently by zidovudine, with protein levels peaking 3 days after induction.…”

Section: Discussionmentioning

confidence: 59%

Gene induction for the treatment of methylmalonic aciduria

Buck

Khaniani

et al. 2009

The Journal of Gene Medicine

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“…[5,6,16] Previous studies have mentioned that MDR-1 protein plays a role in defense mechanisms versus toxic effects of smoking and may be effective in removal of stress metabolites. [17,18] Furthermore, there are studies mentioning its role in cellular regeneration. [19] Shteinberg et al [20] shown that inflammatory response is an important risk factor in AAA, together with genetic predisposition.…”

Section: Discussionmentioning

confidence: 99%

Associations between common 3435 C>T variants of the multi-drug resistance [MDR-1 (ABCB1)] gene and abdominal aortic aneurysm: a pilot study

Manduz¹,

Katrancioglu²,

Karahan³

et al. 2011

Turkish J Thorac Cardiovasc Surg

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Amaç: Bu çalışmada, inflamatuvar süreç ve oksidatif strese karşı rol oynadığı ileri sürülen C3435T multi drug rezistans-1 (MDR-1) gen polimorfizminin AAA'daki etkisi ortaya konuldu. Ça lış ma pla nı: Bu çalışmada servisimizde AAA tanısı konulduktan sonra ameliyat edilen 58 hasta (41 erkek, 17 kadın; ort. yaş 62.9±6.6) ile abdominal bilgisayarlı tomografi taramasında aort çapları normal olarak ölçülen 58 sağlıklı kişinin (38 erkek, 20 kadın; ort. yaş 58.8±11.6 yıl) periferik kan örneklerinde MDR gen mutasyonu tarandı. Bul gu lar: MDR-1 C3435T geni CT varyant (x 2 =5,80, p=0.016) ve MDR-1 C3435T geni TT varyant (x 2 =11.47 p=0.001) polimorfizmleri AAA'lı hastalarda istatistiksel olarak anlamlı bulundu (p<0.05). Demografik bulgular gruplar arasında benzerdi. So nuç:Elde edilen ilk sonuçlar MDR-1 geni T alleli polimorfizminin AAA ile ilişkili olduğunu düşündürmektedir. Bu ve benzeri moleküler çalışmaların AAA etyolojisinin anlaşılmasında gelecekte yapılacak çalışmalara öncü olacağı kanaatindeyiz.Anah tar söz cük ler: Abdominal aort anevrizması; inflamasyon; MDR-1 gen polimorfizmi; revers hibridizasyon.Background:The aim of the study was to reveal the effect of the C3435T MDR-1 gene polymorphism in AAA, which has been postulated to play a role in the inflammatory process and protection against oxidative stress. Methods: In this study, we scanned the MDR gene polymorphisms in peripheral blood samples of the 58 patients (41 males, 17 females; mean age 62.9±6.6 years) whom were operated on after the diagnosis of AAA, and of the 58 healthy individuals (38 males, 20 females; mean age 58.8±11.6 years) have normally measured aorta diameters on abdominal computed tomography scan. Results: We found that MDR-1 C3435T gene CT variant (x 2 = 5.80; p=0.016) and MDR-1 C3435T gene TT variant (x 2 =11.47; p=0.001) polymorphisms was statistically significant in AAA cases (p<0.05). The demographic findings were similar in each group. Conclusion: These obtained preliminary results suggest that the T allele polymorphism of the MDR-1 gene is associated with AAA. We belive that such molecular studies will blaze a trail for future studies on the understanding of AAA etiology.

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Longitudinal effects of thymidine analogues on mtDNA, mtRNA and multidrug resistance (MDR-1) induction in cultured cells

Cited by 16 publications

References 27 publications

BMS-986001, an HIV Nucleoside Reverse Transcriptase Inhibitor, Does Not Degrade Mitochondrial DNA in Long-Term Primary Cultures of Cells Isolated from Human Kidney, Muscle, and Adipose Tissue

BMS-986001, an HIV Nucleoside Reverse Transcriptase Inhibitor, Does Not Degrade Mitochondrial DNA in Long-Term Primary Cultures of Cells Isolated from Human Kidney, Muscle, and Adipose Tissue

Gene induction for the treatment of methylmalonic aciduria

Associations between common 3435 C>T variants of the multi-drug resistance [MDR-1 (ABCB1)] gene and abdominal aortic aneurysm: a pilot study

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