help button home button Am J Pathol International Conference on Pathology of Chest Diseases
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published online as doi:10.2353/ajpath.2008.070613 on February 14, 2008

Published online before print February 14, 2008
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ajpath.2008.070613v1
172/3/681    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Setzer, B.
Right arrow Articles by Walker, U. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Setzer, B.
Right arrow Articles by Walker, U. A.
(American Journal of Pathology. 2008;172:681-690.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070613

Pyrimidine Nucleoside Depletion Sensitizes to the Mitochondrial Hepatotoxicity of the Reverse Transcriptase Inhibitor Stavudine

Bernhard Setzer, Dirk Lebrecht and Ulrich A. Walker

From the Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany

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.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2008 by the American Society for Investigative Pathology.