The influence of nitroheterocyclic radiosensitizers on the membrane of red blood cells.
Nitroimidazole compounds are effective radiosensitizers, but neurotoxic side effects prevent their clinical use. Studying the effect of misonidazole, metronidazole and two of its derivatives, 4.5-NO2-METRO and 4-NO2-METRO, on red blood cell, it was recently demonstrated that these compounds inhibit the red cell membrane (Na+-K+) ATPase and decrease the fluidity of the membrane bilayer. In order to extend these observations and to achieve a more complete interpretation, four additional investigations were selected: the (Ca++-Mg++)ATPase activity, the anion channel (band 3 protein) kinetics, the susceptibility of the phospholipids to peroxidation, and their influence on the concentration of reduced glutathione (GSH). The activity of the (Ca++-Mg++)ATPase and its stimulation by calmodulin were decreased by all four drugs, but the anion transport kinetics were unaltered. No lipid peroxidation could be detected, as estimated by the production of malonyldialdehyde. The red cell GSH was depleted by 4.5-NO2-METRO, probably due to the formation of a complex between GSH and the drugs [Varghese 1983]. The mechanism of the inhibition of the ATPases is not yet clearly apparent; it is presently sought in a direct interaction of the drugs with some thiol reactive groups of the ATPases.
D000838:Anions / Q000097:blood; D017301:Ca(2+) Mg(2+)-ATPase / Q000097:blood; D000252:Calcium-Transporting ATPases / Q000097:blood; D002147:Calmodulin / Q000502:physiology; D004910:Erythrocyte Membrane / Q000187:drug effects*; D005978:Glutathione / Q000097:blood; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008054:Lipid Peroxides / Q000097:blood; D008563:Membrane Lipids / Q000097:blood; D009593:Nitroimidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D000838:Anions; D002147:Calmodulin; D007473:Ion Channels; D008054:Lipid Peroxides; D008563:Membrane Lipids; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D005978:Glutathione