Direct effect of taxol on free radical formation and mitochondrial permeability transition

To elucidate the potential role of mitochondria in Taxol-induced cytotoxici ty, we studied its direct mitochondrial effects. In Percoll-gradient purifi ed liver mitochondria, Taxol induced large amplitude swelling in a concentr ation-dependent manner in the muM range. Opening of the permeability pore w as also confirmed by the access of mitochondrial matrix enzymes for membran e impermeable substrates in Taxol-treated mitochondria. Taxol induced the d issipation of mitochondrial membrane potential (Delta Psi) determined by Rh odamine 123 release and induced the release of cytochrome c from the interm embrane space. All these effects were inhibited by 2.5 muM cyclosporine A. Taxol significantly increased the formation of reactive oxygen species (ROS ) in both the aqueous and the lipid phase as determined by dihydrorhodamine 123 and resorufin derivative. Cytochrome oxidase inhibitor CN-, azide, and NO abrogated the Taxol-induced mitochondrial ROS formation while inhibitor s of the other respiratory complexes and cyclosporine A had no effect. We c onfirmed that the Taxol-induced collapse of Delta Psi and the induction of ROS production occurs in BRL-3A cells. In conclusion, Taxol-induced adenine nucleotide translocase-cyclophilin complex mediated permeability transitio n, and cytochrome oxidase mediated ROS production. Because both cytochrome c release and mitochondrial ROS production can induce suicide pathways, the direct mitochondrial effects of Taxol may contribute to its cytotoxicity. (C) 2001 Elsevier Science Inc.