Photosensitization of mitochondrial cytochrome c oxidase by hematoporphyrin derivative and related porphyrins in vitro and in vivo.
Mitochondrial cytochrome c oxidase activity was inhibited by exposure to hematoporphyrin derivative followed by photoirradiation. Inhibition of enzyme activity in vitro was a dose- and time-related event, the log of percentage inhibition being linear with time. Exposure of mitochondria to hematoporphyrin or hydroxyethylvinyldeuteroporphyrin sensitized mitochondria to photoirradiation, whereas protoporphyrin IX was only weakly active as a photosensitizer for inhibition of cytochrome c oxidase. Mitochondria from mammary glands of pregnant rats showed hematoporphyrin-induced photosensitivity similar to those from R3230AC mammary adenocarcinomas. Mitochondria prepared from tumors of animals given injections of hematoporphyrin derivative in vivo and then photoirradiated in vitro demonstrated considerable sensitivity to light as reflected by significant inhibition of cytochrome c oxidase activity. A side by side comparison of hematoporphyrin derivative with hematoporphyrin, using this in vivo-in vitro experimental protocol, indicated that photosensitivity was retained for a longer time after treatment with hematoporphyrin derivative. Taken together, these data provide a potential mechanism of action, i.e., inhibition of respiration, for porphyrin-induced photosensitivity, and they offer a useful assay to investigate this family of therapeutic agents.
D000818:Animals; D002460:Cell Line; D003576:Electron Transport Complex IV / Q000378:metabolism* / Q000528:radiation effects; D017324:Hematoporphyrin Derivative; D006415:Hematoporphyrins / Q000494:pharmacology*; D007700:Kinetics; D008027:Light; D008321:Mammary Glands, Animal / Q000201:enzymology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D011166:Porphyrins / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D006415:Hematoporphyrins; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D017324:Hematoporphyrin Derivative; D003576:Electron Transport Complex IV