Photosensitizing effects of Photofrin II on the site-selected mitochondrial enzymes adenylate kinase and monoamine oxidase.
The response to Photofrin II-induced photosensitization on the activities of mitochondrial monoamine oxidase (MAO) and adenylate kinase (AK) were studied in order to gain further insight into site specific effects. Utilizing intact mitochondria in vitro, both MAO, located on the cytoplasmic side of the outer mitochondrial membrane, and AK, located in the intermembrane space, were inhibited by exposure to Photofrin II plus light; inhibition was drug-dose and light-dose dependent. However, MAO activity was inhibited to a greater extent than AK; at 35 micrograms/ml of Photofrin II and 160 J/cm2, MAO activity was decreased by 80% whereas AK activity was inhibited by 30%. Higher doses of Photofrin II had no further effect on AK activity. Studies of photosensitization of AK in different mitochondrial preparations demonstrated that inhibition of activity was evident only when mitochondrial membranes containing sequestered porphyrins were present in the reaction mixture. Using an in vivo-in vitro protocol and sampling at 2 to 72 h after administration of 25 mg/kg of Photofrin II, photosensitization of MAO (30% inhibition) was seen at 2 h after drug treatment but inhibition of activity was not observed at later times. AK activity was unchanged over the entire time course. Compared to cytochrome c oxidase, located in the inner mitochondrial membrane and which displayed a sustained inhibition of activity, we suggest that inhibition of MAO or AK activities probably does not contribute to the tumor cytotoxicity under the usual conditions used for photodynamic therapy.
D000263:Adenylate Kinase / Q000032:analysis* / Q000037:antagonists & inhibitors; D000818:Animals; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000032:analysis; D005260:Female; D017324:Hematoporphyrin Derivative; D006415:Hematoporphyrins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000032:analysis*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010770:Phosphotransferases / Q000032:analysis*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D006415:Hematoporphyrins; D008996:Monoamine Oxidase Inhibitors; D011838:Radiation-Sensitizing Agents; D017324:Hematoporphyrin Derivative; D008995:Monoamine Oxidase; D003576:Electron Transport Complex IV; D010770:Phosphotransferases; D000263:Adenylate Kinase