8th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV


San Francisco, California - September 24 - 26, 2006

URIDINE SUPPLEMENTATION WITH MITOCNOL ANTAGONIZES ZALCITABINE-INDUCED HEPATOTOXICITY IN MICE

Antiviral Therapy 2006; 11:L8 (abstract no. 10)

D Lebrecht, YA Vargas-Infante, B Setzer and UA Walker
Medizinische Universitätsklinik, Department of Rheumatology and Clinical Immunology, Freiburg, Germany

OBJECTIVE: Uridine prevents and treats the mitochondrial toxicity of thymidine analogue reverse transcriptase and γ- polymerase inhibitors in a number of in vitro models. In the present study we evaluate if Mitocnol a sugar cane extract with high uridine bioavailability abrogates zalcitabineinduced hepatotoxicity.

METHODS: BalbC mice (7 weeks of age) were divided into groups (n=9) and exposed to zalcitabine (ddC, 0.36 mg/kg/d corresponding to human dosing, adapted for body surface, or 13 mg/kg/d). Mice were treated with or without Mitocnol (0.1 g/kg/d) in the drinking water for 15 weeks. Liver histology and mitochondrial functions were assessed.

RESULTS: Mice treated with Mitocnol alone did not differ from controls with respect to any parameter. One mouse in the zalcitabine high dose group died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with depleted mitochondrial DNA (mtDNA), reduced cytochrome c oxidase activity (COX/SDH ratio) and increased production of reactive oxygen species (ROS), as assessed by malondialdehyde and superoxide content. Mitocnol also attenuated other pathology (Table 1).

CONCLUSIONS: Zalcitabine induces steatothepatitic and fibrotic changes in murine liver. Despite relatively moderate levels of mtDNA depletion, there is a strong impairment of mtDNA-encoded respiratory chain function and upregulated ROS production. Mitocnol attenuates this mitochondrial hepatotoxicity without intrinsic effects.

Table 1. (Abstract 10)
Zalcitabine Zalcitabine
Zalcitabine (0.36 mg/kg/d) Zalcitabine (13 mg/kg/d)
Control Mitocnol (0.36 mg/kg/d) + Mitocnol (13 mg/kg/d) + Mitocnol
Liver weight, g 0.68 ±0.07 0.67 ±0.11 0.73 ±0.11 0.68 ±0.07 0.81 ±0.06‡ 0.70 ±0.10†
Necroinflammatory score 0.1 ±0.3 0.2 ±0.4 3.6 ±1.7‡ 1.9 ±0.6‡† 8.8 ±1.3‡ 4.9 ±1.4‡§
Steatosis score 0 ±0 0 ±0 1.1 ±0.3‡ 0.6 ±0.5‡† 3.4 ±0.9‡ 2.2 ±0.4‡†
Intrahepatic lipids♦ 0.8 ±0.5 0.7 ±0.6 2.3 ±1.4* 1.4 ±0.8*† 5.9 ±1.8‡ 3.0 ±1.3‡§
COX/SDH activity¶ 100 ±17 104 ±15 45 ±15‡ 73 ±24*† 21 ±9‡ 52 ±9‡§
MtDNA copies$ 658 ±101 626 ±104 522 ±105* 607 ±91 413 ±48‡ 543 ±78*§
Malondialdehyde♠ 207 ±78 184 ±37 335 ±114* 215 ±103† 446 ±117‡ 253 ±59§
Superoxide content¶ 100 ±49 101 ±36 207 ±53‡ 116 ±54† 420 ±162‡ 178 ±36*§
Significance (P<0.05) versus controls * and versus no Mitocnol †. Highly significant (P<0.001) versus control ‡ and versus no Mitocnol §. Units: ¶, % of control mean; $, copies/hepatocyte; ♠ , mmol/g tissue; ♦, mg lipid/mg tissue.

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2006-09-24
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