Effects of apricitabine and other nucleoside reverse transcriptase inhibitors on replication of mitochondrial DNA in HepG2 cells.

Abstract:

:Several nucleoside reverse transcriptase inhibitors are associated with mitochondrial toxicity resulting from inhibition of DNA polymerase-gamma. This study compared the effects on mitochondrial DNA of apricitabine (previously referred to as AVX754 or SPD754), a novel cytidine analogue under development for the treatment of human immunodeficiency virus (HIV)-1 infection, and other reverse transcriptase inhibitors. Human HepG2 hepatoblastoma were cultured for up to 16 days with test compounds at concentrations of 0.3-300 microM. Mitochondrial DNA replication was assessed by means of a duplex nucleic acid sequence-based amplification technique, which measures the ratio of the number of mitochondrial DNA copies to the number of genomic DNA copies. Apricitabine and tenofovir had no effect on the mitochondrial DNA content. In contrast, alovudine, zalcitabine, didanosine and stavudine markedly reduced mitochondrial DNA content, whereas abacavir, emtricitabine, lamivudine and zidovudine produced slight increases in mitochondrial DNA, which may reflect an adaptive cellular response to mitochondrial dysfunction. These results suggest that apricitabine shows a favorable mitochondrial toxicity profile, which is important for long-term clinical use. Further studies are warranted to define the clinical implications of these findings.

journal_name

Antiviral Res

journal_title

Antiviral research

authors

de Baar MP,de Rooij ER,Smolders KG,van Schijndel HB,Timmermans EC,Bethell R

doi

10.1016/j.antiviral.2007.05.004

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

68-74

issue

1

eissn

0166-3542

issn

1872-9096

pii

S0166-3542(07)00349-X

journal_volume

76

pub_type

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