In VitroMitochondrial Toxicity of Metacavir, a New Nucleoside Reverse Transcriptase Inhibitor for Treatment of Hepatitis B Virus

Abstract

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 respiratorychain complexes I to IV. Exposure of HepG2 cells to PNA at concentrations up to 50 M for 15 days resulted in no deleterious effect on cell proliferation, levels of lactate or mtDNA, or enzyme activities of respiratorychain complexes I to IV. In contrast, dideoxycytosine at 10 M and zidovudine at 50 M 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 M 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.

w09, a novel autophagy enhancer, induces autophagy-dependent cell apoptosis via activation of the EGFR-mediated RAS-RAF1-MAP2K-MAPK1/3 pathway

“…Then cells were fixed with 2.5% glutaraldehyde in 0.1 M phosphate buffer (pH7.2) at 4 C for 1 h and subsequently postfixed with 2% osmium tetroxide as described previously. 70 Then cells were dehydrated with sequential washes in ethanol and then embedded in Epon812 (SPI, 02660-AB). The samples were then sectioned with a Reichert-Jung ultracut E ultramicrotome 701704 (Leica, Germany) and stained with uranyl acetate and lead citrate.…”

Simultaneous determination of metacavir and its metabolites in rat plasma using high‐performance liquid chromatography with tandem mass spectrometric detection (LC‐MS/MS)

“…As reported previously, metacavir did not have a high risk for potential mitochondrial‐related effects in rhesus monkeys after 3 months of intravenous administration (Zeng et al ., ), and no adverse effect was observed in rhesus monkeys which had been repeatedly dosed with 50 mg/kg per day for 6 months (Chen et al ., ). It is reported that the potential ability of metacavir to interfere with mitochondrial functions is low in vitro (Zhang et al ., ). In addition, treatment with metacavir for 3 months did not alter mitochondrial enzyme activity or mtDNA content in Himalayana marmotas (Zhang et al ., ).…”

In Vitro Anti-hepatitis B Virus Activity of 2′,3′-Dideoxyguanosine

“…The antiviral activity of 2 0 ,3 0 -dideoxyguanosine (DoG) against human immunodeficiency virus (HIV) has been examined since 1990 (Busso et al 1990;Jeffrey et al 2014). DoG has also been demonstrated to have anti-duck hepatitis B virus (DHBV) efficacy in vivo (Chen et al 2007) and a favorable safety profile compared to AZT (Zeng et al 2009;Zhang et al 2010Zhang et al , 2011. However, its antiviral activity against different hepadnaviruses remains unclear.…”