Metabolism, mitochondrial uptake and toxicity of 2', 3'-dideoxycytidine.

Abstract

2',3'-Dideoxycytidine (ddCyd) is a prescription anti-retroviral drug that causes mitochondrial toxicity and peripheral neuropathy. ddCyd is actively phosphorylated by cytosolic deoxycytidine kinase and nucleoside (di)phosphate kinase to the 5'-triphosphate derivative. However, 2',3'-dideoxycytidine 5'-diphosphocholine (ddCDP-choline) was also found in human cells incubated with ddCyd. In this paper we show that ddCDP-choline is produced from dideoxyCTP (ddCTP) and phosphocholine by phosphocholine cytidylyltransferase. dCTP and CTP appear to activate this synthesis in a concentration-dependent manner. Although ddCTP and ddCDP-choline can both enter the mitochondria, ddCDP-choline uptake is more efficient than ddCTP uptake. These data suggest that ddCDP- choline is the ddCyd metabolite that is probably responsible for mitochondrial toxicity. The uptake of ddCTP and ddCDP-choline by mitochondria is inhibited by 3.0 mM l-carnitine in the cell-free system investigated; when added to U937 cells grown in the presence of 0.25 microM ddCyd, 3.0 mM l-carnitine partially abrogated the mitochondrial toxicity of ddCyd.

• Authors: L Rossi, S Serafini, G F Schiavano, A Casabianca, G Vallanti, L Chiarantini, M Magnani
• Journal: The Biochemical journal (Biochem J) Vol. 344 Pt 3 Pg. 915-20 (Dec 15 1999) ISSN: 0264-6021 [Print] England
• PMID: 10585881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Deoxycytosine Nucleotides
• Dideoxynucleotides
• 2',3'-dideoxycytidine diphosphocholine
• Rhodamine 123
• 2'-deoxycytidine 5'-triphosphate
• Cytidine Diphosphate Choline
• Cytidine Triphosphate
• 2',3'-dideoxycytidine 5'-triphosphate
• Zalcitabine
• Choline-Phosphate Cytidylyltransferase
• Carnitine

Topics

• Animals
• Biological Transport
• Carnitine (pharmacology)
• Choline-Phosphate Cytidylyltransferase (metabolism)
• Cytidine Diphosphate Choline (analogs & derivatives, metabolism)
• Cytidine Triphosphate (pharmacology)
• DNA, Mitochondrial (analysis)
• Deoxycytosine Nucleotides (metabolism, pharmacology)
• Dideoxynucleotides
• Humans
• Kinetics
• Mitochondria, Liver (metabolism)
• Rabbits
• Rhodamine 123
• U937 Cells
• Zalcitabine (pharmacology)