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-hepatiti s B virus activity, showed clinical toxicity consistent with mitochond rial dysfunction. In vitro methods were used to understand further thi s toxicity. Using a sensitive and specific radioimmunoassay, FIAU was found to be present in nuclear DNA of human hepatoblastoma cells incub ated for 6 days in 10 or 50 mu M drug, at a level of 1 residue per 63 or 39 thymidines, respectively, and was present in mitochondrial DNA a t a level of 1 residue per 2139 or 1696 thymidines, respectively. Huma n hepatoblastoma cells were incubated for 6 days in increasing concent rations of FIAU or, for comparative purposes, the nucleoside analogue dideoxycytidine (ddC), after which time the cells were examined by ele ctron microscopy. At 10 mu M and higher concentrations, both compounds induced morphological changes in the ultrastructure of mitochondria c haracterized by marked mitochondrial swelling, loss of internal crista e and dissolution of the internal matrix. These results, considered al ong with previously published studies, indicate that FIAU has deleteri ous effects in vitro on mitochondrial function and structure that occu r relatively quickly but without an apparent decrease in the abundance of mitochondrial DNA. Copyright (C) 1996 Elsevier Science Ltd