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Pyrimidine nucleoside depletion sensitizes to the mitochondrial hepatotoxicity of the reverse transcriptase inhibitor stavudine

Setzer, B. and Lebrecht, D. and Walker, U. A.. (2008) Pyrimidine nucleoside depletion sensitizes to the mitochondrial hepatotoxicity of the reverse transcriptase inhibitor stavudine. American Journal of Pathology, Vol. 172, no. 3. pp. 681-690.

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Official URL: http://edoc.unibas.ch/dok/A6004900

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Abstract

Stavudine is a hepatotoxic antiretroviral nucleoside analogue that also inhibits the replication of mitochondrial DNA (mtDNA). To elucidate the mechanism and consequences of mtDNA depletion, we treated HepG2 cells with stavudine and either redoxal, an inhibitor of de novo pyrimidine synthesis, or uridine, from which pyrimidine pools are salvaged. Compared with treatment with stavudine alone, co-treatment with redoxal accelerated mtDNA depletion, impaired cell division, and activated caspase 3. These adverse effects were completely abrogated by uridine. Intracellular ATP levels were unaffected. Transcriptosome profiling demonstrated that redoxal and stavudine acted synergistically to induce CDKN2A and p21, indicating cell cycle arrest in G1, as well as genes involved in intrinsic and extrinsic apoptosis. Moreover, redoxal and stavudine showed synergistic interaction in the up-regulation of transcripts encoded by mtDNA and the induction of nuclear transcripts participating in energy metabolism, mitochondrial biogenesis, oxidative stress, and DNA repair. Genes involved in nucleotide metabolism were also synergistically up-regulated by both agents; this effect was completely antagonized by uridine. Thus, pyrimidine depletion sensitizes cells to stavudine-mediated mtDNA depletion and enhances secondary cell toxicity. Our results indicate that drugs that diminish pyrimidine pools should be avoided in stavudine-treated human immunodeficiency virus patients. Uridine supplementation reverses this toxicity and, because of its good tolerability, has potential clinical value for the treatment of side effects associated with pyrimidine depletion.
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 Investigative Pathology
ISSN:0002-9440
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Nov 2012 16:22
Deposited On:08 Nov 2012 16:16

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