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Uridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in mice†
Article first published online: 22 DEC 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 45, Issue 1, pages 72–79, January 2007
How to Cite
Lebrecht, D., Vargas-Infante, Y. A., Setzer, B., Kirschner, J. and Walker, U. A. (2007), Uridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in mice. Hepatology, 45: 72–79. doi: 10.1002/hep.21490
Potential conflict of interest: Dr. Walker is a consultant for Pharma Nord.
- Issue published online: 22 DEC 2006
- Article first published online: 22 DEC 2006
- Manuscript Accepted: 10 OCT 2006
- Manuscript Received: 4 AUG 2006
- BMBF, Kompetenznetz HIV/AIDS. Grant Number: 01KI0211
Zalcitabine is an antiretroviral nucleoside analogue that exhibits long-term toxicity to hepatocytes by interfering with the replication of mitochondrial DNA (mtDNA). Uridine antagonizes this effect in vitro. In the present study we investigate the mechanisms of zalcitabine-induced hepatotoxicity in mice and explore therapeutic outcomes with oral uridine supplementation. BalbC mice (7 weeks of age, 9 mice in each group) were fed 0.36 mg/kg/d of zalcitabine (corresponding to human dosing adapted for body surface), or 13 mg/kg/d of zalcitabine. Both zalcitabine groups were treated with or without Mitocnol (0.34 g/kg/d), a dietary supplement with high bioavailability of uridine. Liver histology and mitochondrial functions were assessed after 15 weeks. One mouse exposed to high dose zalcitabine died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with abundant mitochondria. The organelles were enlarged and contained disrupted cristae. Terminal transferase dUTP nick end labeling (TUNEL) assays showed frequent hepatocyte apoptosis. mtDNA was depleted in liver tissue, cytochrome c-oxidase but not succinate dehydrogenase activities were decreased, superoxide and malondialdehyde were elevated. The expression of COX I, an mtDNA-encoded respiratory chain subunit was reduced, whereas COX IV, a nucleus-encoded subunit was preserved. Uridine supplementation normalized or attenuated all toxic abnormalities in both zalcitabine groups, but had no effects when given without zalcitabine. Uridine supplementation was without apparent side effects. Conclusion: Zalcitabine induces mtDNA-depletion in murine liver with consequent respiratory chain dysfunction, up-regulated synthesis of reactive oxygen species and microvesicular steatohepatitis. Uridine supplementation attenuates this mitochondrial hepatotoxicity without apparent intrinsic effects. (HEPATOLOGY 2007;45:72–79.)