Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations

Cupler, Edward; Danon, Moris J.; Jay, Cheryl A.; Hench, Karen; Ropka, Mary E.; Dalakas, M. C.

doi:10.1007/s004010050291

Cited by 14 publications

(22 citation statements)

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“…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: 99%

Section: Introductionmentioning

confidence: 99%

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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“…18 Furthermore, this differentiation was accompanied by a decline in ⌬⌿m, ROS production and, unexpectedly, an increase in mitochondrial number. Mitochondrial mass increase preceding cell death has also been observed, e.g., in zidovudine (AZT)-caused myopathy in AIDS patients 35 and upon etoposide treatment of hematopoietic cells. 36 Whether mitochondrial proliferation is a prerequisite for some forms of mitochondrion type apoptosis and how it is controlled remain to be investigated.…”

Section: Epithelial Differentiation At Early Times During Resveratrolmentioning

confidence: 97%

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

et al. 2001

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Resveratrol, a polyphenol present in wine and grapes, can inhibit tumor cell growth in vitro and tumorigenesis in vivo. Some of its effects have been linked to activation of the p53 tumor suppressor; however, p53 is frequently mutated in tumors, particularly in the common and often therapy-resistant colon cancers. Using the human wild-type p53-expressing HCT116 colon carcinoma cell line and HCT116 cells with both p53 alleles inactivated by homologous recombination, we show in the current study that resveratrol at concentrations comparable to those found in some foods can induce apoptosis independently of p53. The cell death is primarily mitochondria-mediated and not receptor-mediated. No cells survived in cultures continuously exposed to 100 M resveratrol for 120 hr. When compared with 5-FU, resveratrol stimulated p53 accumulation and activity only weakly and with delayed kinetics and neither the increased levels nor the activity affected apoptosis detectably. The apoptosis agonist Bax was overproduced in response to resveratrol regardless of p53 status, yet the kinetics of Bax expression were influenced by p53. Remarkably, apoptosis was preceded by mitochondrial proliferation and signs of epithelial differentiation. Thus, resveratrol triggers a p53-independent apoptotic pathway in HCT116 cells that may be linked to differentiation. The antifungal phytoalexin resveratrol (3,5,4Ј-trihydroxy-transstilbene) is a constituent of many plant species and present at particularly high levels in grapes and wine. 1 As a polyphenol, it is not only a potent inhibitor of radical formation (ED 50 27 M) but acts as a pleiotropic effector molecule to inhibit initiation, promotion and progression of malignant transformation. Resveratrol inhibits the cyclooxygenase (ED 50 15 M) and hydroperoxidase (ED 50 3.7 M) activities of COX-1 and the hydroperoxidase activity of COX-2 (ED 50 85 M). 2 Furthermore, it functions as an inhibitor of platelet aggregation, a modulator of lipid and lipoprotein metabolism 3 and an effective blocker of ribonucleotide reductase (ED 50 100 M) that provides deoxyribonucleotides for DNA synthesis. 4 It also inhibits DNA polymerase 5 and mimics estradiol. 6 Several of these activities constitute the basis for the chemopreventive action of resveratrol, exemplified by its antimutagenic activity in the Ames assay, inhibition of tumorigenesis in a 2-stage murine skin-cancer model 2 and inhibition of cell proliferation in vitro. 7,8 The presence of the functional wild-type form of the p53 tumor suppressor correlates with the sensitivity of mouse tumors and at least some human tumors to therapeutic agents. 9 -11 p53 is stabilized and activated as a transcription factor in response to a variety of cellular stresses, 12 the result being either cell-cycle arrest, mostly through transcriptional activation of the p21 WAF/Cip1 inhibitor of cyclin-dependent kinases, or apoptosis, depending on the cell context. Apoptosis often involves changes to mitochondria. 13 One of the major predictive parameters indicating commitment...

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“…In cell lines, ddC, like its two sister nucleoside analogs, AZT and ddI, inhibits the ␥-DNA polymerase of the mitochondrial matrix and terminates, noncompetitively, the nascent mtDNA causing impairment of DNA replication and termination of the mtDNA chain. This, in turn, leads to mtDNA depletion with dysfunction of mtDNAencoded enzymes (Arnaudo et al, 1991;Benbrik et al, 1997;Chen and Cheng, 1989;Chen et al, 1991;Cupler et al, 1995;Dalakas et al, 1990Dalakas et al, , 1994Keilbaugh et al, 1993;Lewis and Dalakas, 1995;Luster et al, 1989;Mhiri et al, 1991). The demonstrated effect of ddC in causing a "mitochondrial DNA-depleting neuropathy" is analogous to the known effect of AZT in causing a "mitochondrial DNA-depleting myopathy" (Arnaudo et Electron microscopy of sural nerve biopsies from patients with ddC-neuropathy demonstrate abnormal mitochondria in the myelinated axons (A to D).…”

Section: Discussionmentioning

confidence: 99%

“…Laboratory Investigation • November 2001 • Volume 81 • Number 11 al, 1991; Bozzette et al, 1991;Cupler et al, 1995;Dalakas et al, 1990Dalakas et al, , 1994Jay et al, 1994;Lamperth et al, 1991;Lewis et al, 1992Lewis et al, , 1994Mhiri et al, 1991). The preferential organ toxicity of these nucleosides appears to be related to the thymidine kinase isoforms responsible for their phosphorylation, or to tissuespecific polymorphisms of mtDNA polymerase-␥ ( Lewis and Dalakas, 1995).…”

Section: Mitochondrial Dna Depletion In Aids Patientsmentioning

confidence: 99%

Mitochondrial Alterations with Mitochondrial DNA Depletion in the Nerves of AIDS Patients with Peripheral Neuropathy Induced by 2′3′-Dideoxycytidine (ddC)

Dalakas

Semino–Mora

Leon‐Monzon

2001

Laboratory Investigation

195

122

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SUMMARY:The 2'3'-dideoxycytidine (ddC), a nonazylated dideoxynucleoside analog used for the treatment of AIDS, causes a dose-dependent, painful, sensorimotor axonal peripheral neuropathy in up to 30% of the patients. To investigate the cause of the neuropathy, we performed morphological and molecular studies on nerve biopsy specimens from well-selected patients with ddC-neuropathy and from control subjects with disease, including patients with AIDS-related neuropathy never treated with ddC. Because ddC, in vitro, inhibits the replication of mitochondrial DNA (mtDNA), we counted the number of normal and abnormal mitochondria in a 0.04 mm 2 cross-sectional area of the nerves and quantified the copy numbers of mtDNA by competitive PCR in all specimens. A varying degree of axonal degeneration was present in all nerves. Abnormal mitochondria with enlarged size, excessive vacuolization, electron-dense concentric inclusions and degenerative myelin structures were prominent in the ddC-neuropathy and accounted for 55% Ϯ 2.5% of all counted mitochondria in the axon and Schwann cells, compared with 9% Ϯ 0.7% of the controls (p Ͻ 0.001). Significantly (p Ͻ 0.005) reduced copy numbers, with as high as 80% depletion, of the mtDNA was demonstrated in the nerves of the ddC-treated patients compared with the controls. We conclude that ddC induces a mitochondrial neuropathy with depletion of the nerve's mtDNA. The findings are consistent with the ability of ddC to selectively inhibit the ␥-DNA polymerase in neuronal cell lines. Toxicity to mitochondria of the peripheral nerve is a new cause of acquired neuropathy induced by exogenous toxins and may be the cause of neuropathy associated with the other neurotoxic antiretroviral drugs or toxic-metabolic conditions. (Lab Invest 2001, 81:1537-1544.

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Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations

Cited by 14 publications

References 0 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

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

Mitochondrial Alterations with Mitochondrial DNA Depletion in the Nerves of AIDS Patients with Peripheral Neuropathy Induced by 2′3′-Dideoxycytidine (ddC)

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