Metabolism, mitochondrial uptake and toxicity of 2′,3′-dideoxycytidine
| Autor: | Mauro Magnani, Anna Casabianca, Giuditta Fiorella Schiavano, Sonja Serafini, Laura Chiarantini, Luigia Rossi, Giuliana Vallanti |
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| Rok vydání: | 1999 |
| Předmět: |
Cytidine Diphosphate Choline
Cytidine Triphosphate Mitochondria Liver Mitochondrion Biology DNA Mitochondrial Biochemistry chemistry.chemical_compound 2'3' dideoxycytidine Carnitine medicine Animals Humans Rhodamine 123 Choline-Phosphate Cytidylyltransferase Molecular Biology Phosphocholine Zalcitabine Kinase Biological Transport U937 Cells Cell Biology Deoxycytidine kinase medicine.disease Molecular biology Kinetics Mitochondrial toxicity Cytosol chemistry Deoxycytosine Nucleotides Rabbits Nucleoside Dideoxynucleotides Research Article |
| Zdroj: | Biochemical Journal. 344:915-920 |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | 2ʹ,3ʹ-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 5ʹ-triphosphate derivative. However, 2ʹ,3ʹ-dideoxycytidine 5ʹ-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 μM ddCyd, 3.0 mM L-carnitine partially abrogated the mitochondrial toxicity of ddCyd. |
| Databáze: | OpenAIRE |
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