The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2',3'-dideoxycytidine.

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2',3'-dideoxycytidine.

J Biol Chem. 1992 Feb 15;267(5):2856-9. Unique Identifier : AIDSLINE MED/92147617
Chen CH; Cheng YC; Department of Pharmacology, Yale University School of Medicine,; New Haven, Connecticut 06510.

Abstract: 2',3'-Dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and shows beneficial effects in AIDS therapy. The compound inhibits mitochondrial DNA (mtDNA) synthesis at a clinically relevant concentration, which could be responsible for the side effects of ddC observed in the clinic. Thymidine (dThd), one of the substrates of mitochondrial deoxypyrimidine kinase (dPyd kinase), was not able to reverse the mitochondrial toxicity of ddC in CEM cells. Furthermore, the cytoplasmic deoxycytidine kinase (dCyd kinase)-deficient CEM cells were highly resistant to the mitochondrial toxicity of ddC. These data suggest a critical role for cytoplasmic dCyd kinase in the mitochondrial toxicity of ddC. The metabolites of ddC, but not ddC itself, were able to inhibit mtDNA synthesis in isolated mitochondria. The potency of the inhibitory effect was in the order of ddCTP greater than ddCDP greater than ddCMP greater than ddC. The lack of inhibition by ddC of mtDNA synthesis could be due to the inefficient ddC phosphorylation in mitochondria. Although the mitochondrial dPyd kinase was reported to phosphorylate ddC, the phosphorylation of ddC in isolated mitochondria was not detectable. The data suggest that ddC is phosphorylated to ddCTP in the cytoplasm and then transported into mitochondria to exert its inhibitory effect on mtDNA synthesis.

Keywords: Cell Division/DRUG EFFECTS Cell Line Cell Survival/DRUG EFFECTS Cytarabine/PHARMACOLOGY Cytoplasm/ENZYMOLOGY Deoxycytidine Kinase/*METABOLISM Drug Resistance DNA Replication/*DRUG EFFECTS DNA, Mitochondrial/*BIOSYNTHESIS Human Kinetics Mitochondria/*DRUG EFFECTS/METABOLISM Thymidine/METABOLISM/PHARMACOLOGY Zalcitabine/*METABOLISM/*PHARMACOLOGY JOURNAL ARTICLE

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