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Clin Pharmacol Ther. 2014 Jul;96(1):110-20. doi: 10.1038/clpt.2014.64. Epub 2014 Mar 17.

Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-γ inhibition.

Author information

1
Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
2
Harvard Medical School and Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
3
Department of Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA.
4
Georgetown University, Washington, DC, USA.
5
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
6
1] Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA [2] Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.

Abstract

We hypothesized that competition between nucleotide reverse-transcriptase inhibitor triphosphate and endogenous deoxyribonucleotide triphosphate (dNTP) may lead to depletion of dNTP pools and mitochondrial dysfunction independent of polymerase-γ (pol-γ) inhibition. We collected peripheral blood mononuclear cells from 75 adults (25 cases: HIV-infected patients with mitochondrial toxicity, 25 HIV-infected positive controls, and 25 HIV-negative controls). We observed statistically significant individual and group differences in ribonucleotide (RN) and deoxyribonucleotide (dRN) pools. The median values for the RN pools were 10,062 (interquartile range (IQR): 7,090-12,590), 4,360 (IQR: 3,058-6,838), and 2,968 (IQR: 2,538-4,436) pmol/10(6) cells for negative controls, positive controls, and cases, respectively. Cases had significantly higher absolute mitochondrial DNA copy number as compared with negative controls (P < 0.05). Moreover, cases had significantly higher expression levels of pol-γ, nucleotide transporters, cellular kinases, and adenosine triphosphate (ATP)-binding cassette (ABC) proteins as compared with controls. Antiretroviral therapy (ART) perturbs RN and dRN pools. Depletion of RN and dRN pools may be associated with ART-induced mitochondrial toxicity independent of pol-γ inhibition.

PMID:
24637942
PMCID:
PMC4065195
DOI:
10.1038/clpt.2014.64
[Indexed for MEDLINE]
Free PMC Article
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