Human inter-individual variability in metabolism and genotoxic response to zidovudine

Olivero, Ofelia A.; Ming, Jessica M.; Das, Shreyasi; Vazquez, Irma L.; Richardson, Diane; Weston, Ainsley; Poirier, Miriam C.

doi:10.1016/j.taap.2007.12.005

Cited by 7 publications

(10 citation statements)

References 26 publications

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“…It is known that thymidine kinase 1 is expressed during S phase in hyperplastic cells, and it appears to be induced in this study by AZT treatment and is reported to be primarily responsible for AZT phosphorylation (33). From this, we propose that much higher levels of AZT-TP are present in neonatal hyperplastic heart tissue than are likely to be observed in adult tissue.…”

Section: Discussionsupporting

confidence: 53%

Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model

Snowdin

Hsiung

Kesterson

et al. 2015

Antimicrob Agents Chemother

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The prevention of mother-to-child transmission (MTCT) of HIV is a crucial component in HIV therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), primarily 3=-azido-3=-thymidine (AZT [zidovudine]), have been used to treat both mothers and neonates. While AZT is being replaced with less toxic drugs in treating mothers in MTCT prevention, it is still commonly used to treat neonates. Problems related to mitochondrial toxicity and potential mutagenesis associated with AZT treatment have been reported in treated cohorts. Yet little is known concerning the metabolism and potential toxicity of AZT on embryonic and neonatal tissues, especially considering that the enzymes of nucleoside metabolism change dramatically as many tissues convert from hyperplastic to hypertrophic growth during this period. AZT is known to inhibit thymidine phosphorylation and potentially alter deoxynucleoside triphosphate (dNTP) pools in adults. This study examines the effects of AZT on dNTP pools, mRNA expression of deoxynucleoside/deoxynucleotide metabolic enzymes, and mitochondrial DNA levels in a neonatal rat model. Results show that AZT treatment dramatically altered dNTP pools in the first 7 days of life after birth, which normalized to agematched controls in the second and third weeks. Additionally, AZT treatment dramatically increased the mRNA levels of many enzymes involved in deoxynucleotide synthesis and mitochondrial biogenesis during the first week of life, which normalized to age-matched controls by the third week. These results were correlated with depletion of mitochondrial DNA noted in the second week. Taken together, results demonstrated that AZT treatment has a powerful effect on the deoxynucleotide synthesis pathways that may be associated with toxicity and mutagenesis. N ucleoside reverse transcriptase inhibitors (NRTIs) are an important class of drug used primarily in treatment of the HIV infection and prevention of mother-to-child transmission (MTCT) of the virus. One of these NRTIs, 3=-azido-3=-thymidine (AZT [zidovudine]), is of interest as it is commonly used as a component of treatment for pregnant mothers and their newborn children. AZT was developed in 1974 as a cancer treatment drug, but in 1984 it was found to be more effective in treating HIV. Since then, it has been a major drug of choice used in highly active antiretroviral therapy (HAART) worldwide in adults, mothers, and their infants (1-3). While it is now being replaced with less toxic drugs, it is still commonly used to treat neonates (4, 5), in which AZT is highly efficient in preventing HIV transmission. AZT is given as a prodrug that must be phosphorylated by the host cell to AZT-triphosphate (AZT-TP), an analogue of TTP, in order to inhibit viral replication. While its metabolism and toxicity in adults have been well characterized, fetal and neonatal metabolism and toxicity have not been studied. Clinical manifestations, including suppression of bone marrow and anemia with low hemoglobin levels, have been reported in AIDS patients treated with ...

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Section: Discussionsupporting

confidence: 53%

Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model

Snowdin

Hsiung

Kesterson

et al. 2015

Antimicrob Agents Chemother

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“…AZT (Sigma-Aldrich Co, St Louis, MO) was dissolved in phosphate buffered saline (PBS) pH 7.2 (Biosource, Rockville, MD) and the final concentration was calculated from absorbance at 266 nm with a molar extinction coefficient of 11,500. Two NHMEC strains were selected for these experiments, based on their ability to incorporate AZT into DNA [19]. Low incorporator (LI) strain M98040 cells and high incorporator (HI) strain M980005 cells were cultured for 6 passages, grown to 75% confluency and exposed in duplicate for 24 hours to 0, 10 or 200 μM AZT.…”

Section: Methodsmentioning

confidence: 99%

Centrosomal amplification and aneuploidy induced by the antiretroviral drug AZT in hamster and human cells

Borojerdi¹,

Ming²,

Cooch³

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The centrosome directs chromosomal migration by a complex process of tubulin-chromatin binding. In this contribution centrosomal abnormalities, including centrosomal amplification, were explored in Chinese Hamster Ovary (CHO) and Normal Human Mammary Epithelial (NHMEC) cells exposed to the antiretroviral drug zidovudine (3'-azido-3'-deoxythymidine, AZT). Centrosomal amplification/fragmentation was observed in both cell types and kinetochore positive micronuclei were found in AZT-exposed CHO cells in correlation with dose. Normal human mammary epithelial cell (NMHEC), strain M99005, previously identified as a strain that incorporates high levels of AZT into DNA (High incorporator, HI), showed greater centrosomal amplification when compared with a second strain, NHMEC M98040, which did not incorporate AZT into DNA (Low incorporator, LI). Additionally, an abnormal tubulin distribution was observed in AZT-exposed HI cells bearing multiple centrosomes. Immunofluorescent staining of human cells with Aurora A, a kinase involved in the maturation of the centrosome, confirmed the induction of centrosomal amplification and revealed multipolar mitotic figures. Flow cytometric studies revealed that cells bearing abnormal numbers of centrosomes and abnormal tubulin distribution had similar S-phase percentages suggesting that cells bearing unbalanced chromosomal segregation could divide. Therefore, AZT induces genomic instability and clastogenicity as well as alterations in proteins involved in centrosomal activation, all of which may contribute to the carcinogenic properties of this compound.

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“…NRTI-exposed M99005 cells exhibited higher numbers of T(−) cells for all treatments when compared to NRTI-exposed M98040 cells. The data suggests that, when treated with an NRTI, the M99005 cells, which are high incorporators of AZT into DNA, are unable to properly polymerize tubulin, but the M98040 cells, which do not incorporate AZT into DNA, have normal tubulin polymerization [Olivero et al, 2008]. …”

Section: Resultsmentioning

confidence: 99%

“…These NHMEC strains have a variable ability to induce thymidine kinase 1, the first enzyme in the metabolic pathway for AZT phosphorylation. Because the M98040 cells do not induce thymidine kinase 1 and do not incorporate AZT into DNA, it is presumed that the damage is associated with inability to polymerize β-tubulin in a normal fashion after exposure to NRTIs [Olivero et al, 2008]. Although 3TC, d4T, and ddI behave in a similar fashion to AZT in halting viral transcription, 3TC and ddI are not phosphorylated by thymidine kinase 1.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study [Borojerdi et al, 2009], AZT was shown, for the first time, to induce centrosome amplification in Chinese Hamster Ovary (CHO) cells and Normal Human Mammary Epithelial Cells (NHMECs). In this study, we report centrosome amplification induced in CHO cells and NHMECs by the NRTIs 3TC, ddI, and d4T; and, for that purpose, CHO cells and two NHMEC strains, M99005 and M98040, have been examined [Olivero et al, 2008]. In addition to centrosome amplification, we found disruptions in tubulin distribution in NHMECs.…”

Section: Introductionmentioning

confidence: 96%

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Centrosome amplification induced by the antiretroviral nucleoside reverse transcriptase inhibitors lamivudine, stavudine, and didanosine

Ward

Poirier

et al. 2009

Environ and Mol Mutagen

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In cultured cells, exposure to the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT) induces genomic instability, cell cycle arrest, micronuclei, sister chromatid exchanges, and shortened telomeres. In previous studies, we demonstrated AZT-induced centrosome amplification (>2 centrosomes/cell). Here, we investigate centrosome amplification in cells exposed to other commonly used NRTIs. Experiments were performed using Chinese Hamster Ovary (CHO) cells, and two Normal Human Mammary Epithelial Cell (NHMEC) strains: M99005 and M98040, which are high and low incorporators of AZT into DNA, respectively. Cells were exposed for 24 hr to lamivudine (3TC), stavudine (d4T), didanosine (ddI), and thymidine, and stained with antipericentrin antibody. Dose response curves were performed to determine cytotoxicity and a lower concentration at near plasma levels and a 10-fold higher concentration were chosen for the experiments. In CHO cells, there was a concentration-dependent, significant (p < 0.05) increase in centrosome amplification for each of the NRTIs. In NHMEC strain M99005, an NRTI-induced increase (p < 0.05) in centrosome amplification was observed for the high concentrations of each NRTI and the low doses of 3TC and ddI. In NHMEC strain M98040, the high doses of ddI and d4T showed significant increases in centrosome amplification. Functional viability of amplified centrosomes was assessed by arresting microtubule nucleation with nocodazole. In cells with > 2 centrosomes, the ability to recover microtubule nucleation was similar to that of unexposed cells. We conclude that centrosome amplification is a consequence of exposure to NRTIs and that cells with centrosome amplification are able to accomplish cell division.

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Human inter-individual variability in metabolism and genotoxic response to zidovudine

Cited by 7 publications

References 26 publications

Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model

Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model

Centrosomal amplification and aneuploidy induced by the antiretroviral drug AZT in hamster and human cells

Centrosome amplification induced by the antiretroviral nucleoside reverse transcriptase inhibitors lamivudine, stavudine, and didanosine

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