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Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside reverse transcriptase inhibitor prodrug

Venhoff, Ana C. and Lebrecht, Dirk and Reuss, Frank U. and Heckl-Ostreicher, Brigitte and Wehr, Roland and Walker, Ulrich A. and Venhoff, Nils. (2009) Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside reverse transcriptase inhibitor prodrug. Antimicrobial agents and chemotherapy : AAC, Vol. 53. pp. 2748-2751.

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Official URL: http://edoc.unibas.ch/dok/A6004651

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Abstract

Fosalvudine tidoxil is a prodrug derived from the nucleoside reverse transcriptase inhibitor 3-deoxy-3-fluorothymidine (FLT; alovudine). FLT effectively inhibits resistant human immunodeficiency virus type 1, but its clinical development was stopped due to bone marrow and liver toxicity. In this study, we examined the long-term in vivo effects of fosalvudine tidoxil on the mitochondrial DNA (mtDNA) contents in rats. Sprague-Dawley rats received fosalvudine tidoxil (15, 40, or 100 mg/kg of body weight/day) by oral gavage during a period of 8 weeks. Didanosine (100 mg/kg/day) was used as a positive control for mitochondrial toxicity. mtDNA levels in liver, gastrocnemius muscle, sciatic nerve, and inguinal fat pad tissues were quantified by real-time PCR. In hepatic mitochondria, fosalvudine tidoxil induced significant mtDNA depletion. At doses of 15, 40, and 100 mg/kg, the mean hepatic mtDNA values were 62, 64, and 47% of control values, respectively. Rats exposed to 100 mg/kg of fosalvudine tidoxil, unlike all other groups, had slightly elevated levels of glutamate pyruvate transaminase in sera. Didanosine induced a loss of mtDNA (to 48% of the control level) similar to that induced by fosalvudine tidoxil. mtDNA levels in skeletal, neural, and adipose tissues in the negative control and treatment groups were similar. Our results suggest that fosalvudine tidoxil induces mitochondrial hepatotoxicity and that this effect warrants scrutiny in clinical trials.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Rheumatologie
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Rheumatologie
UniBasel Contributors:Walker, Ulrich A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Mar 2013 11:14
Deposited On:01 Mar 2013 11:13

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