Fialuridine is phosphorylated and inhibits DNA synthesis in isolated rat hepatic mitochondria.
Fialuridine (FIAU) is a thymidine analog effective against hepatitis B virus. Toxicity associated with FIAU treatment included clinical signs consistent with mitochondrial dysfunction, including severe lactic acidosis. To understand further the mechanism of FIAU toxicity, we examined the effect of FIAU on DNA synthesis in mitochondria. Mitochondria isolated from livers of naive rats were treated in vitro with concentrations of FIAU or FIAU triphosphate (FIAU-TP) ranging from 0.1 to 200 microM. A 14 or 32% decrease in mitochondrial DNA synthesis compared to controls was observed when isolated mitochondria were treated with 25 microM FIAU or FIAU-TP, respectively. Since it is thought that nucleosides must be phosphorylated to inhibit DNA polymerase, studies were conducted to determine whether isolated rat mitochondria could phosphorylate FIAU. Results using lanthanum chloride precipitation and HPLC analysis showed that enzymes present in a mitochondrial lysate were capable of phosphorylating FIAU to form FIAU monophosphate.
Horn
D M
DM
Toxicology Research Laboratories, Lilly Research Laboratories, Indianapolis, IN 46140, USA.
Neeb
L A
LA
Colacino
J M
JM
Richardson
F C
FC
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C043457:fialuridine