Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells

Eric, Benbrik; Chariot, Patrick; Bonavaud, Sylvie; Ammi-Saı̈d, Mustapha; Frisdal, Éric; Rey, Christiane; Gherardi, Romain K.; Barlovatz-Meimon, Georgia

doi:10.1016/s0022-510x(97)05376-8

Cited by 168 publications

(95 citation statements)

References 28 publications

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“…Subsequent work in HIV negative rat models treated with AZT confirmed the presence of the same type of toxicities in the rat [11,15]. Cytotoxicity of AZT has also been shown in a variety of transformed cells, including the HepG2 cell line [10,22,27]. In all cases, the toxicity of AZT was correlated with abnormal mitochondria and mitochondrial DNA depletion, when examined.…”

Section: Discussionmentioning

confidence: 79%

“…During the pre-highly active antiretroviral therapy (HAART) era, AZT monotherapy in AIDS patients was closely associated with myopathy, cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10]. Subsequent work in HIV negative rat models treated with AZT confirmed the presence of the same type of toxicities in the rat [11,15].…”

Section: Discussionmentioning

confidence: 99%

“…AZT capitalizes on human immunodeficiency virus's (HIV) unique method of replication by inhibiting the viral reverse transcriptase, which blocks the life-cycle of HIV and effectively slows the progression of AIDS. When given in monotherapy at high doses over long periods of time, AZT is known to cause damage to many tissues, including a mitochondrial skeletal muscle myopathy, a dilated cardiomyopathy, and hepatotoxicity [1][2][3][4][5][6][7][8][9][10][11]. These conditions are related to AZT use and not to the progression of AIDS since when patients experiencing one or more of these adverse effects discontinued AZT therapy, the adverse effects would resolve [8,9].…”

Section: Introductionmentioning

confidence: 99%

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3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Lynx

Bentley

McKee

2006

Biochemical Pharmacology

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Abstract3′-Azido-3′-deoxythymidine (AZT) is a staple of highly active antiretroviral therapy (HAART). Prior to HAART, long-term use of high-dosage AZT caused myopathy, cardiomyopathy, and hepatotoxicity, associated with mitochondrial DNA depletion. As a component of HARRT, AZT causes cytopenias and lipodystrophy. AZT-5′-triphosphate (AZTTP) is a known inhibitor of the mitochondrial polymerase γ and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart mitochondria, AZT phosphorylation beyond AZT-5′-monophosphate (AZTMP) was not detected. Rather, AZT was shown to be a more potent inhibitor of thymidine phosphorylation (50% inhibitory concentration (IC 50 ) of 7.0 ± 1.0 μM) than AZTTP is of polymerase γ (IC 50 of >100 μM), suggesting that depletion of mitochondrial stores of TTP may limit replication. This work has investigated whether an identical mechanism might account for the hepatotoxicity seen with long-term use of AZT. Isolated rat liver mitochondria were incubated with labeled thymidine or AZT, and the rate and extent of phosphorylation were determined by HPLC analysis of acid-soluble extracts of the incubated mitochondria. The results showed that in the phosphorylation of thymidine to TMP, liver mitochondria exhibit a higher V max and K m than heart mitochondria, but otherwise heart and liver mitochondria display similar kinetics. AZT is phosphorylated to AZTMP, but no further phosphorylated forms were detected. In addition, AZT inhibited the production of TTP, with an IC 50 of 14.4 ± 2.6 μM AZT. This is higher, but comparable to, the results seen in isolated rat heart mitochondria. KeywordsAZT; Liver mitochondria; Thymidine; Mitochondrial toxicity; Thymidine kinase 2; Reverse transcriptase inhibitors Abbreviations AIDS, acquired immunodeficiency syndrome; AZT, 3′-azido-3′-deoxythymidine; AZTDP, 3′-azido-3′-deoxythymidine-5′-diphosphate; AZTMP, 3′-azido-3′-deoxythymidine-5′-monophosphate; AZTTP, 3′-azido-3′-deoxythymidine-5′-triphosphate; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; IC 50 , 50% inhibitory concentration; S.E.M., standard error of mean

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

Lynx

Bentley

McKee

2006

Biochemical Pharmacology

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“…The latter two products would be expected to be transported into mitochondria by the DNC, there to inhibit the synthesis of mtDNA by competing with dNTPs for the active site of the DNA polymerase-␥ and by chain termination (21). Clinical and laboratory findings have shown that the mechanism of toxicity of most antiviral and anticancer nucleoside analogs is to impair mitochondrial function (17,20,(22)(23)(24)(25). In fact, the main side effects of these drugs, myopathy, cardiomiopathy, polyneuropathy, and lactic acidosis, greatly resemble the spectrum of clinical manifestations seen in inherited mitochondrial diseases (26).…”

Section: Discussionmentioning

confidence: 99%

The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

Dolce

Fiermonte

Runswick

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

182

157

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The synthesis of DNA in mitochondria requires the uptake of deoxynucleotides into the matrix of the organelle. We have characterized a human cDNA encoding a member of the family of mitochondrial carriers. The protein has been overexpressed in bacteria and reconstituted into phospholipid vesicles where it catalyzed the transport of all four deoxy (d) NDPs, and, less efficiently, the corresponding dNTPs, in exchange for dNDPs, ADP, or ATP. It did not transport dNMPs, NMPs, deoxynucleosides, nucleosides, purines, or pyrimidines. The physiological role of this deoxynucleotide carrier is probably to supply deoxynucleotides to the mitochondrial matrix for conversion to triphosphates and incorporation into mitochondrial DNA. The protein is expressed in all human tissues that were examined except for placenta, in accord with such a central role. The deoxynucleotide carrier also transports dideoxynucleotides efficiently. It is likely to be medically important by providing the means of uptake into mitochondria of nucleoside analogs, leading to the mitochondrial impairment that underlies the toxic side effects of such drugs in the treatment of viral illnesses, including AIDS, and in cancer therapy.

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“…As current clinical guidelines recommend combined therapy, usually including NRTI (Centers for Disease Control and Prevention, 1999), such regimens may be important to the development of mitochondrial toxicity in new tissue targets as treatment is prolonged because of the increased longevity of patients with AIDS. [The following references were cited only in Table 1: Barile et al, 1994Barile et al, , 1997Benbrik et al, 1997;Browne et al, 1993;Chen and Cheng, 1992;Cherrington et al, 1995;Corcuera et al, 1996;Cui et al, 1997;Dalakas et al, 1990;Elimadi et al, 1997. The following references were cited only in Table 1: Feldman and Anderson, 1994;Feldman et al, 1992;Hart et al, 1992;Hertzberg et al, 1992;Hobbs et al, 1992Hobbs et al, , 1995; Institute of Medicine (US) Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials, 1995;Izuta et al, 1991.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Lewis

Copeland

Day

2001

Laboratory Investigation

159

111

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Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells

Cited by 168 publications

References 28 publications

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

3′-Azido-3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: A possible mechanism of AZT hepatotoxicity

The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

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