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Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity.

Publication ,  Journal Article
Chen, CH; Vazquez-Padua, M; Cheng, YC
Published in: Mol Pharmacol
May 1991

The anti-human immunodeficiency virus (-HIV) nucleoside analogs azidothymidine (AZT), dideoxycytidine (ddC), dideoxyinosine (ddl), dideoxydidehydrothymidine (D4T), and dideoxydidehydrocytidine (D4C) and the anticancer drug cytosine arabinoside (AraC) were compared for their effects on the mitochondrial DNA (mtDNA) content in a human lymphoblastoid cell line, CEM. The potency of these compounds in reducing mtDNA content was in the order of ddC greater than D4C greater than D4T greater than AZT greater than ddl. AraC did not have a significant effect on mtDNA content. All of the compounds tested, except AraC, stimulated lactic acid production at concentrations that inhibited mtDNA synthesis. The action of ddC and ddl occurred at concentrations that did not affect cell growth significantly in 4 days but retarded cell growth by day 6. D4T and D4C decreased mtDNA content by 50% at doses lower than those that inhibited cell growth by 50% in 4 days (ID50). However, AZT required a dose higher than the ID50 to exert similar effects on mtDNA content. The decrease of mtDNA content caused by ddC also occurred in nerve growth factor-treated PC12 cells, which differentiate to neuron-like cells upon treatment with nerve growth factor. The preferential inhibition of mtDNA, compared with cell growth, by some of these anti-HIV nucleoside analogs correlates well with their ability to cause drug-limiting delayed toxicity, such as peripheral neuropathy, in patients. These data suggest that the selective mitochondrial toxicity could be responsible for the delayed toxicity caused by these anti-HIV analogs.

Duke Scholars

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

May 1991

Volume

39

Issue

5

Start / End Page

625 / 628

Location

United States

Related Subject Headings

  • Zidovudine
  • Zalcitabine
  • T-Lymphocytes
  • Stavudine
  • Pharmacology & Pharmacy
  • Nucleosides
  • Lymphocyte Activation
  • Humans
  • HIV
  • Dideoxynucleosides
 

Citation

APA
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ICMJE
MLA
NLM
Chen, C. H., Vazquez-Padua, M., & Cheng, Y. C. (1991). Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol, 39(5), 625–628.
Chen, C. H., M. Vazquez-Padua, and Y. C. Cheng. “Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity.Mol Pharmacol 39, no. 5 (May 1991): 625–28.

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

May 1991

Volume

39

Issue

5

Start / End Page

625 / 628

Location

United States

Related Subject Headings

  • Zidovudine
  • Zalcitabine
  • T-Lymphocytes
  • Stavudine
  • Pharmacology & Pharmacy
  • Nucleosides
  • Lymphocyte Activation
  • Humans
  • HIV
  • Dideoxynucleosides