Mitochondrial toxicity of cationic photosensitizers for photochemotherapy.
The triarylmethane derivative Victoria Blue-BO (VB-BO) and the chalcogenapyrylium (CP) dyes have potential for use in photochemotherapy, because they are taken up by the mitochondria of malignant cells and cause cell death. To clarify the mechanism of cell killing we examined the phototoxic effects of VB-BO and a series of three CP dyes on bioenergetic function in isolated rat liver mitochondria. Without photoirradiation, and irrespective of the respiratory substrate used, each of the compounds tested induced some uncoupling of oxidative phosphorylation. Visible irradiation of VB-BO produced an inhibition of mitochondrial respiration when glutamate plus malate, but not succinate, was used as the respiratory substrate. With photoirradiation VB-BO was also shown to inhibit rotenone-sensitive NADH-cytochrome c reductase activity, but it had no effect on succinate-cytochrome c reductase activity. These data indicate that photoactivation of VB-BO produces selective inhibition of mitochondrial respiratory complex I. Photoirradiation of the CP dyes inhibited both complex I and complex II initiated respiratory activity. With photoirradiation, the CP dyes also inhibited both NADH- and succinate-cytochrome c reductase activities, as well as other membrane-bound enzymes, cytochrome c oxidase and succinate dehydrogenase, but not the mitochondrial matrix enzyme, citrate synthetase, or the cytosolic enzyme, lactate dehydrogenase. alpha-Tocopherol protected bioenergetic activities against CP dye photodamage. These results suggest that mitochondrial photosensitization by CP compounds is mediated by the production of membrane-damaging singlet oxygen which causes nonspecific damage to membranes and membrane-bound enzymes.
Modica-Napolitano
J S
JS
Department of Biology, Tufts University, Medford, Massachusetts 02155.
Joyal
J L
JL
Ara
G
G
Oseroff
A R
AR
Aprille
J R
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000494:pharmacology*; D004396:Coloring Agents / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D007700:Kinetics; D008293:Malates / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000378:metabolism; D009930:Organic Chemicals; D016566:Organoselenium Compounds; D010101:Oxygen Consumption / Q000187:drug effects*; D010778:Photochemotherapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012643:Selenium / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013691:Tellurium / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D004396:Coloring Agents; D005971:Glutamates; D008293:Malates; D009930:Organic Chemicals; D016566:Organoselenium Compounds; D011838:Radiation-Sensitizing Agents; C060012:chalogenapyrylium dye 8b; D014810:Vitamin E; C041370:victoria blue; D013384:Succinate Cytochrome c Oxidoreductase; D013385:Succinate Dehydrogenase; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D012643:Selenium; D013691:Tellurium