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

Autor: Musie Ghebremichael, Wing Lam, Regina Edifor, Yung-Chi Cheng, Allison Langs-Barlow, Shanmugapriya Selvaraj, Min Li, Yram Foli, Lydia Barakat, Elizabeth Tubridy, Arit Ogbuagu, Elijah Paintsil
Rok vydání: 2013
Předmět:
Male
Mitochondrial DNA
Anti-HIV Agents
Deoxyribonucleotides
Gene Dosage
Endogeny
HIV Infections
DNA-Directed DNA Polymerase
Biology
Mitochondrion
Peripheral blood mononuclear cell
DNA
Mitochondrial
Article
nucleoside transporters
polymerase gamma
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Deoxyribonucleotide Triphosphate
medicine
Humans
mitochondrial toxicity
Pharmacology (medical)
030212 general & internal medicine
030304 developmental biology
Nucleic Acid Synthesis Inhibitors
Pharmacology
0303 health sciences
human immunodeficiency virus
Kinase
Nucleotides
cellular kinases
Middle Aged
Ribonucleotides
medicine.disease
Molecular biology
3. Good health
DNA Polymerase gamma
Mitochondria
Mitochondrial toxicity
ATP-Binding Cassette proteins
chemistry
Case-Control Studies
Nucleotide Transport Proteins
Reverse Transcriptase Inhibitors
ATP-Binding Cassette Transporters
Female
Adenosine triphosphate
Zdroj: Clinical pharmacology and therapeutics
ISSN: 1532-6535
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: