BISPHOSPHONATES ARE INCORPORATED INTO ADENINE-NUCLEOTIDES BY HUMAN AMINOACYL-TRANSFER-RNA SYNTHETASE ENZYMES

Bisphosphonates are synthetic pyrophosphate analogues and are therapeu tic inhibitors of bone resorption, although their exact mechanisms of action are unclear. Some bisphosphonates can be metabolised into non-h ydrolysable ATP analogues by Dictyostelium discoideum amoebae, in a ba ck-reaction catalysed by several Class II aminoacyl-tRNA synthetases. We have found that the same enzymes in cell-free extracts of several h uman cell lines are also capable of metabolising in vitro the same bis phosphonates that are metabolised by Dictyostelium. These results indi cate that human cells, following drug internalisation, should be capab le of metabolising certain bisphosphonates. The toxic effects of these bisphosphonates towards bone-resorbing osteoclasts may therefore be d ue to accumulation of non-hydrolysable ATP analogues or inhibition of aminoacyl-tRNA synthetase enzymes. (C) 1996 Academic Press, Inc.