Metabolism, mitochondrial uptake and toxicity of 2', 3'-dideoxycytidine.
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.
Rossi
L
L
Institute of Biochemistry 'G. Fornaini', University of Urbino, 61029-Urbino, Italy.
Serafini
S
S
Schiavano
G F
GF
Casabianca
A
A
Vallanti
G
G
Chiarantini
L
L
Magnani
M
M
D000818:Animals; D001692:Biological Transport; D002331:Carnitine / Q000494:pharmacology; D019916:Choline-Phosphate Cytidylyltransferase / Q000378:metabolism; D003566:Cytidine Diphosphate Choline / Q000031:analogs & derivatives / Q000378:metabolism; D003570:Cytidine Triphosphate / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000032:analysis; D003845:Deoxycytosine Nucleotides / Q000378:metabolism / Q000494:pharmacology; D054306:Dideoxynucleotides; D006801:Humans; D007700:Kinetics; D008930:Mitochondria, Liver / Q000378:metabolism*; D011817:Rabbits; D020112:Rhodamine 123; D020298:U937 Cells; D016047:Zalcitabine / Q000494:pharmacology*
D004272:DNA, Mitochondrial; D003845:Deoxycytosine Nucleotides; D054306:Dideoxynucleotides; C083199:2',3'-dideoxycytidine diphosphocholine; D020112:Rhodamine 123; C024107:2'-deoxycytidine 5'-triphosphate; D003566:Cytidine Diphosphate Choline; D003570:Cytidine Triphosphate; C037406:2',3'-dideoxycytidine 5'-triphosphate; D016047:Zalcitabine; D019916:Choline-Phosphate Cytidylyltransferase; D002331:Carnitine