Oxic and anoxic photodamage triggered at the subcellular level by the synergistic action of haematoporphyrin derivative and nitroimidazoles.

Abstract

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.