Nucleoside reverse transcriptase inhibitors (NRTIs)-induced expression profile of mitochondria-related genes in the mouse liver

Desai, Varsha G.; Lee, Taewon; Delongchamp, Robert R.; Leakey, Julian E.A.; Lewis, Sherry M.; Lee, Fei; Moland, Carrie L.; Branham, William S.; Fuscoe, James C.

doi:10.1016/j.mito.2008.01.002

Cited by 30 publications

(23 citation statements)

References 57 publications

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“…NRTIs can result in altered gene expression profiles. 50,51 Altered gene expression profiles have been observed in the absence of mitochondrial DNA depletion, suggesting that NRTIs can cause mitochondrial dysfunction and not inhibit mitochondrial DNA polymerase gamma. 52 The association of tenofovir with mitochondrial dysfunction has been investigated.…”

Section: Mechanisms Of Tenofovir-associated Bone Lossmentioning

confidence: 99%

Tenofovir-associated bone density loss

Mansky¹

2009

TCRM

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Section: Mechanisms Of Tenofovir-associated Bone Lossmentioning

confidence: 99%

Tenofovir-associated bone density loss

Mansky¹

2009

TCRM

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“…13 Previous studies illustrate NRTI-induced mitochondrial toxicity that causes serious adverse effects ranging from lactic acidosis to hepatic steatosis during long-term HAART treatment. 14,15 On the other hand, NNRTIs bind to an allosteric hydrophobic site, approximately 10 Å away from the polymerase active site, which is unique to HIV-1 RT and absent in host cell polymerases. 16 Therefore, unlike NRTIs, NNRTIs specifically target RT while excluding any binding interaction with other polymerases.…”

Section: Introductionmentioning

confidence: 99%

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Bailey

Sullivan²,

Iyidogan³

et al. 2013

J. Med. Chem.

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Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.

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“…While these data were obtained using a suprapharmacological dose modeled on earlier rodent studies (15,28), they nevertheless provide proof of principle of potential toxicity to human neonates. Clearly, further in vivo studies must be conducted to establish a dose-response analysis.…”

Section: Discussionmentioning

confidence: 99%

“…The animal treatment schedule corresponds to the treatment schedule in humans corrected for rat gestation and life span. The AZT dose was modeled after earlier rat and mouse studies (15,28). While this is a suprapharmacological dose, it was done to limit the number of animals required for a proof-of-principle study.…”

Section: Methodsmentioning

confidence: 99%

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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Nucleoside reverse transcriptase inhibitors (NRTIs)-induced expression profile of mitochondria-related genes in the mouse liver

Cited by 30 publications

References 57 publications

Tenofovir-associated bone density loss

Tenofovir-associated bone density loss

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

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

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