In vitro mitochondrial toxicity of metacavir, a new nucleoside reverse transcriptase inhibitor for treatment of hepatitis B virus.
Therapy with nucleoside reverse transcriptase inhibitors (NRTIs) can be associated with mitochondrial toxicity. In vitro studies have been used to predict the predisposition for and characterize the mechanisms causing mitochondrial toxicity. Metacavir (PNA) is a novel synthetic nucleoside analog for oral administration with potent and specific antiviral activity against hepatitis B virus (HBV). We assessed the potential for mitochondrial toxicity of PNA in long-term cultures of HepG2 hepatoma cells by measuring mitochondrial function (through lactate secretion), levels of mitochondrial DNA (mtDNA), and the activities of respiratory-chain complexes I to IV. Exposure of HepG2 cells to PNA at concentrations up to 50 μM for 15 days resulted in no deleterious effect on cell proliferation, levels of lactate or mtDNA, or enzyme activities of respiratory-chain complexes I to IV. In contrast, dideoxycytosine at 10 μM and zidovudine at 50 μM have significant effects on cell proliferation, levels of lactate and mtDNA, and enzyme activities of respiratory-chain complexes I to IV. However, PNA at a supratherapeutic concentration of 250 μM could result in significant alterations in the levels of mtDNA and the activities of respiratory-chain complex enzymes, revealing evidence of the potential mitochondrial toxicity of PNA. In summary, these in vitro results indicate that the potential for PNA to interfere with mitochondrial functions is low.
Zhang
Pinghu
P
Jiangsu Center for New Drug Screening and National Drug Screening Laboratory, China Pharmaceutical University, Nanjing, People's Republic of China.
Zhang
Luyong
L
Jiang
Zhenzhou
Z
Wang
Tao
T
Chen
Hongkui
H
Xiong
Yating
Y
Li
Zhan
Z
D000998:Antiviral Agents / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000235:genetics; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics; D011684:Purine Nucleosides / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
C529213:2-amino-9-(2,3-dideoxy-2,3-dihydroarabinofuranosyl)-6-methoxy-9H-purine; D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D011684:Purine Nucleosides; D018894:Reverse Transcriptase Inhibitors
Ann Neurol. 1991 Jun;29(6):606-14
1892364
Antimicrob Agents Chemother. 1994 Dec;38(12):2743-9
7695256
HIV Med. 2003 Jul;4(3):287-92
12859329
Antivir Ther. 2003 Oct;8(5):463-70
14640394
J Clin Invest. 1995 Feb;95(2):555-63
7860738
Antimicrob Agents Chemother. 2002 Mar;46(3):716-23
11850253
Am J Hum Genet. 1991 Mar;48(3):502-10
1847791
Brain. 1996 Aug;119 ( Pt 4):1357-64
8813297
N Engl J Med. 1990 Apr 19;322(16):1098-105
2320079
J Neurol Sci. 1997 Jul;149(1):19-25
9168161
Ann Neurol. 1994 Apr;35(4):482-7
8154877
Clin Ther. 2000 Aug;22(8):911-36; discussion 898
10972629
Mol Pharmacol. 1991 May;39(5):625-8
1851960
Crit Care Med. 1997 Aug;25(8):1425-30
9267960
Antimicrob Agents Chemother. 2000 Mar;44(3):496-503
10681309
Sex Transm Infect. 2001 Jun;77(3):158-73
11402222
Anal Biochem. 1976 May 7;72:248-54
942051
AIDS. 2000 Feb 18;14(3):F25-32
10716495
Antimicrob Agents Chemother. 2007 Jul;51(7):2531-9
17470651
Antimicrob Agents Chemother. 2008 Feb;52(2):598-605
18056280
J Viral Hepat. 2003 Jan;10(1):50-4
12558912
J Biol Regul Homeost Agents. 2003 Apr-Jun;17(2):166-71
14518717
Lancet. 2000 Oct 21;356(9239):1423-30
11052597
AIDS. 1998 Oct 1;12(14):1735-44
9792373
Acta Pharmacol Sin. 2009 Dec;30(12):1666-73
19915582
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Mar 15;864(1-2):9-14
18316251
J Clin Virol. 2005 May;33(1):60-4
15797366
Neuropathol Appl Neurobiol. 1995 Dec;21(6):540-7
8745244
Toxicol In Vitro. 2006 Aug;20(5):535-46
16406476