Reference

Cellular metabolism of 2',3'-dideoxycytidine, a compound active against human immunodeficiency virus in vitro

Cellular metabolism of 2',3'-dideoxycytidine, a compound active against human immunodeficiency virus in vitro. Starnes, Milbrey Cate; Cheng, Yung Chi (Sch. Med., Univ. North Carolina, Chapel Hill, NC 27514, USA). J. 104086-76-2 and 104086-75-1 are also occured in this study. Biol. Chem., 262(3), 988-91 (English) 1987. CODEN: JBCHA3. ISSN: 0021-9258. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The nucleoside analog 2',3'-dideoxycytidine (ddCyd) [7481-89-2] has been shown to inhibit the infectivity and cytopathic effect of human immunodeficiency virus on human OKT4+ lymphocytes in vitro. Metab. of ddCyd by human T-lymphoblastic cells (Molt 4) neg. for human immunodeficiency virus and OKT4 was examd. Molt 4 cells accumulated ddCyd and its phosphorylated derivs. into acid sol. and acid-insol. material in a dose-dependent manner. For each concn. tested, 2',3'-dideoxycytidine triphosphate [66004-77-1] represented 40% of the total acid-sol. pool of ddCyd metabolites. Uptake of 5 mM ddCyd was linear for 4 h after addn. of drug. Efflux of ddCyd metabolites from cells followed a biphasic course with an initial retention half-life of 2.6 h for 2',3'-dideoxycytidine triphosphate. DNA, but not RNA, of cells incubated with [3H]ddCyd became radiolabeled. Nuclease and phosphatase treatment of DNA followed by reverse-phase HPLC showed that the nucleoside was incorporated into DNA in its original form. DdCyd was not susceptible to deamination by human deoxycytidine deaminase [37259-56-6]. It was a poor substrate for human cytoplasmic and mitochondrial dCyd kinase [9039-45-6], with KM values of 180 and 120 mM, resp. DNA polymerase [9012-90-2] a, b, and g varied in their sensitivities to inhibition by ddCTP with Ki values of 110, 2.6, and 0.016 mM, resp.; however, inhibition was competitive with dCTP in each case. .

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

The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2',3'-dideoxycytidine.Some chemicals with cas registry numbers like 50-89-5 and 104086-76-2 are also used. Chen, Chin Ho; Cheng, Yung Chi (Sch. Med., Yale Univ., New Haven, CT 06510, USA). J. Biol. Chem., 267(5), 2856-9 (English) 1992. CODEN: JBCHA3. ISSN: 0021-9258. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) 2',3'-Dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and shows beneficial effects in AIDS therapy. The compd. inhibits mitochondrial DNA (mtDNA) synthesis at a clin. relevant concn., which could be responsible for the side effects of ddC obsd. 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 crit. 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 > ddCDP > ddCMP > 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. .