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 sign s consistent with mitochondrial dysfunction, including severe lactic a cidosis. To understand further the mechanism of FIAU toxicity, we exam ined the effect of FIAU on DNA synthesis in mitochondria. Mitochondria isolated from livers of naive rats were treated in vitro with concent rations of FIAU or FIAU triphosphate (FIAU-TP) ranging from 0.1 to 200 mu M. A 14 or 32% decrease in mitochondrial DNA synthesis compared to controls was observed when isolated mitochondria were treated with 25 mu M FIAU or FIAU-TP, respectively. Since it is thought that nucleosi des must be phosphorylated to inhibit DNA polymerase, studies were con ducted to determine whether isolated rat mitochondria could phosphoryl ate FIAU. Results using lanthanum chloride precipitation and HPLC anal ysis showed that enzymes present in a mitochondrial lysate were capabl e of phosphorylating FIAU to form FIAU monophosphate. (C) 1997 Elsevie r Science B.V.