Photoactivation enhances the mitochondrial toxicity of the cationic rhodacyanine MKT-077.
In this study, the mitochondrial phototoxicity of the cationic rhodacyanine MKT-077 was investigated by comparing its effects on the inhibition of mitochondrial respiration and the structural integrity of mitochondrial DNA (mtDNA) in the presence and absence of added high-intensity visible light (7.5 J/cm2). Results indicate that photoirradiation significantly enhances the mitochondrial toxicity of MKT-077 at both the biochemical and DNA levels. For example, the concentration of MKT-077 required to achieve one-half maximal inhibition of ADP-stimulated respiration was observed to be 6-fold lower in the presence versus absence of high-intensity light (one-half maximal inhibition at 2.5 versus 15 microg MKT-077/ mg, respectively). In addition, photoirradiation produced a 25-fold increase in inhibition of succinate-cytochrome c reductase activity by MKT-077 (one-half maximal inhibition at 2 versus 50 microg MKT-077/ml, +/-light, respectively) and a 6-fold increase in inhibition of cytochrome oxidase activity (one-half maximal inhibition at 5 versus 30 microg MKT-077/ml, +/-light, respectively). Furthermore, the combination of 25 microg/ml MKT-077 and 7.5 J/cm2 visible light caused significant degradation of mtDNA in isolated rat liver mitochondria, whereas the same concentration of dye in the absence of light had only a modest effect on mtDNA. Evaluation of light-induced MKT-077 lipid peroxidation in mitochondrial membrane fragments by the thiobarbituric acid test and by measurement of nonrespiratory-linked oxygen uptake suggests that mitochondrial phototoxicity by MKT-077 may be the result of lipid peroxidation via reactive oxygen species. These results have important implications with regard to the potential use of MKT-077 in photochemotherapy.
Modica-Napolitano
J S
JS
Department of Biology, Merrimack College, North Andover, Massachusetts 01845, USA.
Brunelli
B T
BT
Koya
K
K
Chen
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000528:radiation effects; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D000882:Haplorhini; D008027:Light; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D009245:NADH Dehydrogenase / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology* / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019802:Succinic Acid / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology* / Q000528:radiation effects
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D011725:Pyridines; D013844:Thiazoles; C097880:MKT 077; D019802:Succinic Acid; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV