DEPLETION OF MITOCHONDRIAL-DNA, DESTRUCTION OF MITOCHONDRIA, AND ACCUMULATION OF LIPID DROPLETS RESULT FROM FIALURIDINE TREATMENT IN WOODCHUCKS (MARMOTA-MONAX)

Fialuridine (FIAU, oxy-2-fluoro-beta-D-arabinofuranosyl)-5-ioduracil) is toxic to liver, heart, muscle, and nerve in clinical trials for chr onic viral hepatitis (CH). Mitochondrial toxicity was hypothesized. To address pathophysiologic mechanisms, we examined mitochondrial change s in FIAU-treated woodchucks (WC) with CH from woodchuck hepatitis vir us infection. WC (with and without CH from woodchuck hepatitis virus i nfection) were treated with FIAU (1.5 mg/kg/day) for 12 weeks. WC were killed. Liver, heart, skeletal muscle, and kidney samples underwent D NA extraction and were analyzed ultrastructurally (transmission electr on microscopy). Myocardium, skeletal muscles, and liver samples were a nalyzed histologically. Abundance of hepatic, myocardial, muscle, and kidney mtDNA decreased in FIAU-treated WC, but the magnitude varied. m tDNA decreased 55% in heart, 65% in kidney, 74% in liver, and 87% in m uscle (p < 0.02 for each tissue: FIAU-treated versus FIAU-untreated). Cellular damage was characterized ultrastructurally by mitochondrial e nlargement, cristae dissolution, and lipid droplets. Lipid droplets fo und in the heart, diaphragm, biceps, and liver were sufficient to iden tify FIAU-treated WC (p < 0.05 each). Widespread mitochondrial damage to many tissues resulted from chronic FIAU treatment and occurred irre spective of CH. It manifested with mtDNA depletion, intracytoplasmic l ipid droplets, and destroyed mitochondrial cristae. Defective mtDNA re plication with mtDNA depletion seems central to the subcellular pathop hysiology of altered energy metabolism and multiorgan failure in FIAU toxicity.