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Antimicrobial Agents and Chemotherapy, April 2007, p. 1142-1149, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01227-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Zidovudine Inhibits Thymidine Phosphorylation in the Isolated Perfused Rat Heart{triangledown}

Delia Susan-Resiga,{dagger} Alice T. Bentley, Matthew D. Lynx, Darcy D. LaClair, and Edward E. McKee*

Indiana University School of Medicine—South Bend, South Bend, Indiana 46617, and the University of Notre Dame, Notre Dame, Indiana 46556

Received 29 September 2006/ Returned for modification 28 November 2006/ Accepted 4 January 2007

Zidovudine (AZT; 3'-azido-3'-deoxythymidine), a thymidine analog, has been a staple of highly active antiretroviral therapy. It is phosphorylated in the host to the triphosphate and functions by inhibiting the viral reverse transcriptase. However, long-term use of AZT is linked to various tissue toxicities, including cardiomyopathy. These toxicities are associated with mitochondrial DNA depletion, which is hypothesized to be caused by AZT triphosphate inhibition of mitochondrial DNA polymerase {gamma}. In previous work with isolated heart mitochondria, we demonstrated that AZT phosphorylation beyond the monophosphate was not detected and that AZT itself was a potent inhibitor of thymidine phosphorylation. This suggests an alternative hypothesis in which depletion of the TTP pool may limit mitochondrial DNA replication. The present work extends these studies to the whole cell by investigating the metabolism of thymidine and AZT in the intact isolated perfused rat heart. [3H]thymidine is converted to [3H]TTP in a time- and concentration-dependent manner. The level of [3H]TMP is low, suggesting that the reaction catalyzed by thymidine kinase is the rate-limiting step in phosphorylation. [3H]AZT is converted in a time- and concentration-dependent manner to AZT monophosphate, the only phosphorylated product detected after 3 h of perfusion. Both compounds display negative cooperativity, similar to the observations with cloned and purified mitochondrial thymidine kinase 2. The presence of AZT in the perfusate inhibits the phosphorylation of [3H]thymidine with a 50% inhibitory concentration of 24 ± 4 µM. These data support the hypothesis that AZT-induced mitochondrial cardiotoxicity may be caused by a limiting pool of TTP that lowers mitochondrial DNA replication.

* Corresponding author. Mailing address: Indiana University School of Medicine—South Bend, South Bend, IN 46617. Phone: (574) 631-7193. Fax: (574) 631-7821. E-mail: McKee.6{at}nd.edu

{triangledown} Published ahead of print on 12 January 2007.

{dagger} Present address: Departments of Biochemistry and Medicine, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1142-1149, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01227-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lynx, M. D., LaClair, D. D., McKee, E. E. (2009). Effects of Zidovudine and Stavudine on Mitochondrial DNA of Differentiating 3T3-F442a Cells Are Not Associated with Imbalanced Deoxynucleotide Pools. Antimicrob. Agents Chemother. 53: 1252-1255 [Abstract] [Full Text]  
  • Hanes, J. W., Johnson, K. A. (2007). A novel mechanism of selectivity against AZT by the human mitochondrial DNA polymerase. Nucleic Acids Res 35: 6973-6983 [Abstract] [Full Text]  


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