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Entecavir (ETV) is an approved deoxyguanosine nucleoside for the treatment of chronic hepatitis B virus (HBV) infection that exhibits potent activity against viral reverse transcriptase. We assessed the potential for mitochondrial toxicity of ETV in long-term cultures of HepG2 hepatoma cells by measuring mitochondrial function (through lactate secretion), levels of mitochondrial DNA (mtDNA), and levels of mitochondrial proteins COX II and COX IV. Furthermore, we tested the activity of ETV-triphosphate (ETV-TP) against mitochondrial DNA polymerase \u03b3 (Pol \u03b3) in vitro. ETV concentrations as high as 100 times the maximal clinical exposure (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) did not affect cell proliferation, levels of lactate, mitochondrial DNA, or mitochondrial proteins throughout the 15-day culture. The lack of mitochondrial toxicity was consistent with the finding that ETV-TP was not recognized by mitochondrial DNA Pol \u03b3 and failed to be incorporated into DNA or inhibit the polymerase assay at the highest levels tested, 300 \u03bcM. Combinations of ETV with each of the other HBV NRTI antivirals, adefovir, tenofovir, and lamivudine at 10 times their respective<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>levels also failed to result in cellular or mitochondrial toxicity. In summary, cell culture and enzymatic studies yielded no evidence that would predict mitochondrial toxicity of ETV at exposure levels in excess of those expected to be achieved clinically.<\/jats:p>","DOI":"10.1128\/aac.01122-07","type":"journal-article","created":{"date-parts":[[2007,12,4]],"date-time":"2007-12-04T01:34:37Z","timestamp":1196732077000},"page":"598-605","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":46,"title":["Entecavir for Treatment of Hepatitis B Virus Displays No In Vitro Mitochondrial Toxicity or DNA Polymerase Gamma Inhibition"],"prefix":"10.1128","volume":"52","author":[{"given":"Charles E.","family":"Mazzucco","sequence":"first","affiliation":[{"name":"Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Hamatake","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Colonno","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Tenney","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2893.2003.00399.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.3.716-723.2002"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"14689","DOI":"10.1016\/S0021-9258(18)47850-7","volume":"262","year":"1987","unstructured":"Boosalis, M. 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