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Photoactivation Enhances the Mitochondrial Toxicity of the Cationic Rhoadcyanine MKT-077

Department of Biology, Merrimack College, North Andover, Massachusetts 01845 [J. S. M-N.]; Department of Biology, Tufts University, Medford, Massachusetts 02155 [J. S. M-N., B. T. B.]; and Division of Cellular and Molecular Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [K. K., L. B. C.]

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 µg 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 µg MKT-077/ml, ±light, respectively) and a 6-fold increase in inhibition of cytochrome oxidase activity (one-half maximal inhibition at 5 versus 30 µg MKT-077/ml, ±light, respectively). Furthermore, the combination of 25 µg/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.

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Received 6/13/97. Accepted 10/23/97.

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