title: Basis for the selective cytotoxicity of rhodamine 123.
abstract: Using rat liver mitochondria we determined that the primary biochemical target for inhibition of mitochondrial bioenergetic function by rhodamine 123 (Rh123) was FoF1-ATPase and that the amount of Rh123 associated with mitochondria is proportional to the mitochondrial membrane potential. Inhibition of coupled respiration by Rh123 in mitochondria isolated from CX-1, a Rh123-sensitive carcinoma cell type, and CV-1, a Rh123-insensitive normal epithelial cell type, was linearly related to the amount of Rh123 added (micrograms/mg protein) with CX-1 mitochondria exhibiting 2-fold greater inhibition compared to CV-1 mitochondria at any given amount of dye. The inhibition pattern for mitochondria isolated from MIP101, a Rh123-insensitive carcinoma cell type, was nonlinear, exhibiting greater sensitivity than CV-1 mitochondria at very low amounts of Rh123 but becoming less sensitive than either CV-1 or CX-1 at higher amounts. Rh123 inhibited FoF1-ATPase activity to a similar extent and in a concentration-dependent manner in both CV-1 and CX-1 mitochondria, but a different and complex pattern of inhibition was apparent for MIP101 mitochondria. Moreover, mitochondria from the 2 carcinoma cell types, CX-1 and MIP101, had higher membrane potentials (163 +/- 7 and 158 +/- 8 mV, respectively) than did mitochondria from the normal epithelial cell type, CV-1 (104 +/- 9 mV). It was concluded that differences in both mitochondrial membrane potential and sensitivity of FoF1-ATPase contribute to the selective cytotoxicity exhibited by Rh123 for certain cell types in vitro.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D051381:Rats; D020112:Rhodamine 123; D012235:Rhodamines / Q000494:pharmacology*; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D012235:Rhodamines; D014966:Xanthenes; D020112:Rhodamine 123; D006180:Proton-Translocating ATPases