The kinetic effects on thymidine kinase 2 by enzyme-bound dTTP may explain the mitochondrial side effects of antiviral thymidine analogs

Antimicrobial Agents and Chemotherapy

Volumn 55, Issue 6, 2011, Pages 2552-2558

  Wang, Liya ^a   Sun, Ren ^a   Eriksson, Staffan ^a  

^a UPPSALA UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

3' FLUOROTHYMIDINE; DEOXYCYTIDINE; LAMIVUDINE; MITOCHONDRIAL DNA; STAVUDINE; THYMIDINE; THYMIDINE DERIVATIVE; THYMIDINE KINASE; THYMIDINE KINASE 2; UNCLASSIFIED DRUG; ZIDOVUDINE;

ANTIVIRAL ACTIVITY; ARTICLE; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INCUBATION TIME; MICROBIAL KINETICS; MITOCHONDRIAL TOXICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION;

ANIMALS; ANTIVIRAL AGENTS; DIDEOXYNUCLEOSIDES; FEMALE; KINETICS; MITOCHONDRIA; PHOSPHORYLATION; RATS; RATS, SPRAGUE-DAWLEY; THYMIDINE KINASE; THYMINE NUCLEOTIDES; ZIDOVUDINE;

EID: 79956300922     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.00109-11     Document Type: Article

References (27)

1. Arnaudo, E., et al. 1991. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 337:508-510.
2. Barroso, J. F., M. Elholm, and T. Flatmark. 2003. Tight binding of deoxyribonucleotide triphosphates to human thymidine kinase 2 expressed in Escherichia coli. Purification and partial characterization of its dimeric and tetrameric forms. Biochemistry 42:15158-15169.
3. Barwick, T., B. Bencherif, J. M. Mountz, and N. Avril. 2009. Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation. Nucl. Med. Commun. 30:908-917.
4. Brinkman, K., J. Smeitink, J. Romijn, and P. Reiss. 1999. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354:1112-1115. (Pubitemid 29452832)
5. Brinkman, K., H. ter Hofstede, D. Burger, J. Meitink, and P. Koopmans. 1998. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 12:1735-1744.
6. Chariot, P., et al. 1999. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J. Hepatol. 30:150-160.
7. Fischer, J. C., et al. 1986. Estimation of NADH oxidation in human skeletal muscle mitochondria. Clin. Chim. Acta 155:263-273.
8. Flexner, C. C., et al. 1994. Relationship between plasma concentrations of 3′-deoxy-3′-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials. J. Infect. Dis. 170:1394-1403.
9. Hosseini, S. H., et al. 2007. Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) alters mitochondrial DNA (mtDNA) and mitochondrial polypeptide abundance: transgenic TK2, mtDNA, and antiretrovirals. Am. J. Pathol. 170:865-874.
10. Lynx, M. D., A. T. Bentley, and E. E. McKee. 2006. 3′-Azido- 3′-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: a possible mechanism of AZT hepatotoxicity. Biochem. Pharmacol. 71:1342-1348.
11. Lynx, M. D., and E. E. McKee. 2006. 3′-Azido-3′- deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria. Biochem. Pharmacol. 72:239-243.
12. Montaner, J. S., et al. 2004. Nucleoside-related mitochondrial toxicity among HIV-infected patients receiving antiretroviral therapy: insights from the evaluation of venous lactic acid and peripheral blood mitochondrial DNA. Clin. Infect. Dis. 38(Suppl. 2):S73-S79.
13. Moraes, C., et al. 1991. mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am. J. Hum. Genet. 48:492-501.
14. Morris, G. W., T. A. Iams, K. G. Slepchenko, and E. E. McKee. 2009. Origin of pyrimidine deoxynucleotide pools in perfused rat heart: implications for 3′-azido-3′-deoxythymidine-dependent cardiotoxicity. Biochem. J. 422:513-520.
15. Munch-Petersen, B., L. Cloos, G. Tyrsted, and S. Eriksson. 1991. Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. J. Biol. Chem. 266:9032-9038.
16. Nolan, D., et al. 2003. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 17:1329-1338. (Pubitemid 36819847)
17. Reiss, P., et al. 2004. Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine + didanosine or zidovudine + zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors. HIV Med. 5:11-14. (Pubitemid 38219975)
18. Saada, A., A. Shaag, and O. Elpeleg. 2003. mtDNA depletion myopathy: elucidation of the tissue specificity in the mitochondrial thymidine kinase (TK2) deficiency. Mol. Genet. Metab. 79:1-5.
19. Saada, A., et al. 2001. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat. Genet. 29:342-344.
20. Susan-Resiga, D., A. T. Bentley, M. D. Lynx, D. D. Laclair, and E. E. McKee. 2007. Zidovudine inhibits thymidine phosphorylation in the isolated perfused rat heart. Antimicrob. Agents Chemother. 51:1142-1149.
21. Traut, T. 1994. Physiological concentrations of purines and pyrimidines. Mol. Cell. Biochem. 140:1-22.
22. Turk, B., R. Awad, E. Usova, I. Bjork, and S. Eriksson. 1999. A pre-steady-state kinetic analysis of substrate binding to human recombinant deoxycytidine kinase: a model for nucleoside kinase action. Biochemistry 38:8555-8561.
23. Venhoff, A. C., D. Lebrecht, F. U. Reuss, B. Heckl-Östreicher, R. Wehr, U. A. Walker, and N. Venhoff. 2009. Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside reverse transcriptase inhibitor prodrug. Antimicrob. Agents Chemother. 53:2748-2751.
24. Walker, U. A., et al. 2004. Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine. Hepatology 9:311-317. (Pubitemid 38222171)
25. Wang, L., and S. Eriksson. 2000. Cloning and characterization of full length mouse thymidine kinase 2: the N-terminal sequence directs import of the precursor protein into mitochondria. Biochem. J. 351:469-476.
26. Wang, L., et al. 1999. Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates. FEBS Lett. 443:170-174. (Pubitemid 29078626)
27. Wang, L., A. Saada, and S. Eriksson. 2003. Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy. J. Biol. Chem. 278:6963-6968.