Fialuridine (FIAU, 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil) is toxic to liver, heart, muscle, and nerve in clinical trials for chronic viral
hepatitis (CH). Mitochondrial toxicity was hypothesized. To address pathophysiologic mechanisms, we examined mitochondrial changes in
FIAU-treated woodchucks (WC) with CH from woodchuck hepatitis virus
infection. WC (with and without CH from woodchuck hepatitis virus
infection) were treated with
FIAU (1.5 mg/kg/day) for 12 weeks. WC were killed. Liver, heart, skeletal muscle, and kidney samples underwent
DNA extraction and were analyzed ultrastructurally (transmission electron microscopy). Myocardium, skeletal muscles, and liver samples were analyzed histologically. Abundance of hepatic, myocardial, muscle, and kidney
mtDNA decreased in
FIAU-treated WC, but the magnitude varied.
mtDNA decreased 55% in heart, 65% in kidney, 74% in liver, and 87% in muscle (p < 0.02 for each tissue:
FIAU-treated versus
FIAU-untreated). Cellular damage was characterized ultrastructurally by mitochondrial enlargement, cristae dissolution, and lipid droplets. Lipid droplets found in the heart, diaphragm, biceps, and liver were sufficient to identify
FIAU-treated WC (p < 0.05 each). Widespread mitochondrial damage to many tissues resulted from chronic
FIAU treatment and occurred irrespective of CH. It manifested with
mtDNA depletion, intracytoplasmic lipid droplets, and destroyed mitochondrial cristae. Defective
mtDNA replication with
mtDNA depletion seems central to the subcellular pathophysiology of altered energy metabolism and multiorgan failure in
FIAU toxicity.