A computational model of mitochondrial AZT metabolism.
The mechanisms of the mitochondrial toxicity of AZT (azidothymidine; zidovudine) are not clear. The two main contenders are the incorporation of phosphorylated AZT into the mtDNA (mitochondrial DNA) and the competitive inhibition of natural deoxynucleotide metabolism. We have built a computational model of AZT metabolism in mitochondria in order to better understand these toxicity mechanisms. The model includes the transport of non-phosphorylated and phosphorylated forms of AZT into mitochondria, phosphorylation, and incorporation into mtDNA. The model also includes the mitochondrial metabolism of the natural deoxynucleotides. We define three simulated cell types, i.e. rapidly dividing, slowly dividing and postmitotic cells. Our standard simulation indicates that incorporation of AZT into mtDNA is highest in rapidly dividing cells because of the higher mitochondrial AZTTP (3'-azidothymidine-5'-triphosphate)/dTTP ratio in this cell type. However, under these standard conditions the rate of incorporation into mtDNA is too low to be a major cause of toxicity. These simulations relied on the assumption that phosphorylated AZT is transported with the same kinetics as phosphorylated thymidine. In simulations with mitochondria set to have a limited ability to transport phosphorylated AZT, AZTTP accumulates to toxic levels in the mitochondria of postmitotic cells, while low levels are maintained in mitochondria from rapidly dividing cells. This result is more consistent with the tissue toxicities observed in patients. Our model also predicts that inhibition by AZT of mitochondrial deoxycytidine phosphorylation by thymidine kinase 2 may contribute to the mitochondrial toxicity, since in simulations using a typical peak plasma AZT level the mtDNA replication rate is decreased by 30% in postmitotic cell simulations.
Bradshaw
Patrick C
PC
Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Li
Jiaxin
J
Samuels
David C
DC
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D001693:Biological Transport, Active; D003198:Computer Simulation; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D015215:Zidovudine / Q000378:metabolism*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015215:Zidovudine