Oxic and anoxic photodamage triggered at the subcellular level by the synergistic action of haematoporphyrin derivative and nitroimidazoles.
A first attempt to impair a biological function by the synergistic effects of HpD and nitroimidazoles (metronidazole or misonidazole) under anaerobic conditions is reported. A function tightly linked to a membrane has been chosen as model and the Ca2+ movements through the inner mitochondrial membrane have been studied. When isolated mitochondria (1 mg/cm3) are irradiated in oxic condition with 25 micrograms/cm3 HpD and 1 mmol dm-3 nitroimidazole in the medium, Ca2+ uptake is stopped after 15 s of irradiation. When irradiated in anoxic conditions with 25 micrograms/cm3 HpD alone, addition of ATP triggers a normal Ca2+ uptake even after 10 min of irradiation. In contrast Ca2+ uptake is stopped by 1 min irradiation after addition of 1 mmol dm-3 misonidazole to HpD and by 2 min irradiation after addition of 1 mmol dm-3 metronidazole. Thus, under these experimental conditions, the enhancement ratio of the HpD action (defined as the ratio of the durations of irradiation necessary to obtain the cessation of Ca2+ uptake before and after addition of a component other than HpD) is of the order of 40, 10 and 5 for oxygen, misonidazole and metronidazole, respectively. Misonidazole is still efficient at a concentration of 0.1 mmol dm-3.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000332:Aerobiosis / Q000187:drug effects / Q000528:radiation effects; D000693:Anaerobiosis / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000528:radiation effects; D004357:Drug Synergism; D017324:Hematoporphyrin Derivative; D006415:Hematoporphyrins / Q000494:pharmacology*; D008795:Metronidazole / Q000494:pharmacology; D008920:Misonidazole / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000528:radiation effects; D009593:Nitroimidazoles / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D006415:Hematoporphyrins; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D008795:Metronidazole; D017324:Hematoporphyrin Derivative; D008920:Misonidazole; D000255:Adenosine Triphosphate; D002118:Calcium