Incorporation of fialuridine (FIAU) into mitochondrial DNA and effects of FIAU on the morphology of mitochondria in human hepatoblastoma cells.
Fialuridine (FIAU), a thymidine nucleoside analogue with anti-hepatitis B virus activity, showed clinical toxicity consistent with mitochondrial dysfunction. In vitro methods were used to understand further this toxicity. Using a sensitive and specific radioimmunoassay, FIAU was found to be present in nuclear DNA of human hepatoblastoma cells incubated for 6 days in 10 or 50 n M drug, at a level of 1 residue per 63 or 39 thymidines, respectively, and was present in mitochondrial DNA at a level of 1 residue per 2139 or 1696 thymidines, respectively. Human hepatoblastoma cells were incubated for 6 days in increasing concentrations of FIAU or, for comparative purposes, the nucleoside analogue dideoxycytidine (ddC), after which time the cells were examined by electron microscopy. At 10 mum and higher concentrations, both compounds induced morphological changes in the ultrastructure of mitochondria characterized by marked mitochondrial swelling, loss of internal cristae and dissolution of the internal matrix. These results, considered along with previously published studies, indicate that FIAU has deleterious effects in vitro on mitochondrial function and structure that occur relatively quickly but without an apparent decrease in the abundance of mitochondrial DNA.
Colacino
J M
JM
Infectious Diseases Research, Lilly Research Laboratories, Indianapolis, IN USA; Toxicology Research Laboratories, Lilly Research Laboratories, Greenfield, IN 46285-0438, USA.
Horn
J W
JW
Horn
D M
DM
Richardson
F C
FC