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Antiretroviral Therapy–Induced Mitochondrial Toxicity: Potential Mechanisms Beyond Polymerase‐γ Inhibition
Author(s) -
Selvaraj S,
Ghebremichael M,
Li M,
Foli Y,
LangsBarlow A,
Ogbuagu A,
Barakat L,
Tubridy E,
Edifor R,
Lam W,
Cheng YC,
Paintsil E
Publication year - 2014
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2014.64
Subject(s) - mitochondrial toxicity , toxicity , mitochondrial dna , biology , abacavir , deoxyribonucleotide , microbiology and biotechnology , pharmacology , mitochondrion , chemistry , nucleotide , biochemistry , medicine , viral load , antiretroviral therapy , virology , human immunodeficiency virus (hiv) , gene
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. Clinical Pharmacology & Therapeutics (2014); 96 1, 110–120. doi: 10.1038/clpt.2014.64