Abstract
Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-γ hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-γ) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-γ with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations. The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, and ddI (activated to ddA) and the activated forms of the analogs 3TC, TDF, AZT, FTC, and ABC. These predictions are supported by experimental and clinical data showing significantly greater mtDNA depletion in cell culture and patient samples caused by the di-deoxy analog drugs. For zidovudine (AZT) we calculated a very low mtDNA replication termination probability, in contrast to its reported mitochondrial toxicity in vitro and clinically. Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication.
Highlights
Current guidelines for highly active anti-retroviral treatment (HAART) regimens of HIV-positive patients recommend two drugs of the nucleoside reverse transcriptase inhibitor (NRTI) class (Table 1) [1]
Possible pol-c mediated pathways include the direct inhibition of pol-c by NRTI-triphosphate without incorporation of the analog; chain termination by incorporation of NRTI triphosphate into mitochondrial DNA (mtDNA); and incorporation without chain termination of the analogtriphosphate allowing it to remain as a point mutation in mtDNA
The specific definition of strand termination used in this model raises the hypothesis that dissociation of polymerase-c after an NRTI is incorporated into the mtDNA strand is a critical step in strand termination
Summary
Current guidelines for highly active anti-retroviral treatment (HAART) regimens of HIV-positive patients recommend two drugs of the nucleoside reverse transcriptase inhibitor (NRTI) class (Table 1) [1]. This class currently consists of: stavudine (d4T), lamivudine (3TC), zidovudine (AZT), zalcitabine (ddC), didanosine (ddI), abacavir (ABC), emtricitabine (FTC) and tenofovir (TDF, a nucleotide analog). Though zalcitabine (ddC) at the time of this writing is still technically approved for treatment its distribution in the United States was discontinued by Roche in 2006 In their activated tri-phosphorylated forms, each NRTI acts as a nucleotide analog interacting with the HIV viral reverse transcriptase as an alternative substrate to the natural nucleotides [2,3]. In this paper we consider the plausibility of the currently most widely accepted hypothesis for the toxicity mechanism for this class of drugs; interference of mitochondrial DNA replication by the activated drug
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