Zalcitabine is a synthetic 2′,3′-dideoxycytidine nucleoside analog and nucleoside reverse-transcriptase inhibitor[1]. Zalcitabine is phosphorylated intracellularly to 2′,3′-dideoxycytidine triphosphate, which competes with deoxycytidine triphosphate (dCTP) for incorporation by reverse transcriptase and terminates viral deoxyribonucleic acid (DNA) chain elongation; incorporation by mitochondrial DNA polymerase gamma can also reduce mitochondrial DNA replication[1,2]. Zalcitabine is used in research on reverse-transcriptase biology, nucleoside-analog metabolism, mitochondrial DNA depletion, and nucleoside-analog-associated neuropathic pain models[1-5].
In vitro, Zalcitabine treatment of human hepatocellular carcinoma HepG2 cells (1μM and 5μM; 4, 10, and 14 days) reduced mitochondrial DNA abundance to 15% and 11% of the corresponding controls on day 4 and to less than 1% of the controls on day 14, respectively. Zalcitabine treatment of rat embryonic cardiomyoblast H9c2 cells (1μM and 5μM; 12 days) did not alter mitochondrial DNA abundance[2].
In vivo, Zalcitabine administration to rats (50mg/kg; single intraperitoneal injection; assessment on days 7 and 14) induced sustained mechanical allodynia and increased tumor necrosis factor-alpha (TNF-α) signaling in dorsal root ganglia[3].
References:[1] Hanes JW, Johnson KA. Exonuclease removal of dideoxycytidine (zalcitabine) by the human mitochondrial DNA polymerase. Antimicrob Agents Chemother. 2008;52(1):253-258. doi:10.1128/AAC.00799-07.
[2] Lund KC, Peterson LL, Wallace KB. Absence of a universal mechanism of mitochondrial toxicity by nucleoside analogs. Antimicrob Agents Chemother. 2007;51(7):2531-2539. doi:10.1128/AAC.00039-07.
[3] Zheng X, Ouyang H, Liu S, Mata M, Fink DJ, Hao S. TNF-alpha is involved in neuropathic pain induced by nucleoside reverse transcriptase inhibitor in rats. Brain Behav Immun. 2011;25(8):1668-1676. doi:10.1016/j.bbi.2011.06.003.
[4] Wallace VCJ, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, et al. Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain. Brain. 2007;130(10):2688-2702. doi:10.1093/brain/awm195.
[5] Maratou K, Wallace VCJ, Hasnie FS, Okuse K, Hosseini R, Jina N, et al. Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV-associated neuropathic pain. Eur J Pain. 2009;13(4):387-398. doi:10.1016/j.ejpain.2008.05.008.