ABSTRACT
The interaction of a series of eight local anaesthetics with cytochrome oxidase chosen as a membrane model protein has been studied with fluorescence technique using quinacrine as a fluorescent probe. The existence of hydrophobic interactions with a non polar region of cytochrome oxidase complex has been shown. The ability of the drug molecules to displace quinacrine bound to cytochrome oxidase correlate as closely with their anaesthetic potency as with their octanol-water partition coefficient. Our results are in good agreement with a recent model of local anaesthetic action on nerve membranes presenting a site of anaesthesia including both lipid binding and protein binding environments.
Subject(s)
Anesthetics, Local , Electron Transport Complex IV , Fluorescence , Quinacrine , SolubilitySubject(s)
Folic Acid Antagonists , Methotrexate/pharmacology , Animals , Kidney/enzymology , Liver/enzymology , Male , MiceABSTRACT
Changes in mouse brain homogenates oxygen uptake are determined, following intraperitoneal injection of misonidazole (100 or 500 mg/kg), at one of four circadian stages. An analysis of periodic regressions of the observed data shows that the circadian variability of brain oxygen utilization is affected by the timing of drug administration.
Subject(s)
Brain/metabolism , Circadian Rhythm/drug effects , Misonidazole/pharmacology , Nitroimidazoles/pharmacology , Oxygen Consumption/drug effects , Animals , Brain/drug effects , Male , MiceABSTRACT
Intraperitoneal doses of Misonidazole were administered at 15.00 hours and 03.00 hours to Balb c/cenlco mice standardized in controlled environmental cages for 3 weeks before the experiment. Non linear pharmacokinetic and temporal variations in the apparent half life were obtained at higher doses.
Subject(s)
Misonidazole/metabolism , Nitroimidazoles/metabolism , Animals , Circadian Rhythm , Female , Half-Life , Kinetics , Mice , Mice, Inbred BALB C , Time FactorsABSTRACT
Using a polarographic method, we studied the inhibition of mitochondrial electron transport at the cytochrome c oxidase site caused by eight local anaesthetics. The diversity of the types of inhibition observed indicate the importance of electrostatic interactions between the anaesthetic molecules and the membrane protein. A linear relationship was recognized between the anaesthetic activity of infiltration and the affinity for the enzyme. We also observed a significant relationship between this affinity and the octanol-water partition coefficient. This result suggests that lipophilic interactions are involved in cytochrome oxidase-anaesthetic binding. We tried to establish a parallel between this binding and the mechanism of anaesthesia involving the nerve membrane proteins.
Subject(s)
Anesthetics, Local/pharmacology , Electron Transport Complex IV/antagonists & inhibitors , Binding, Competitive , Kinetics , Polarography , Structure-Activity RelationshipABSTRACT
Oral administration of cadmium to female rats for 6 weeks does not reduce the microsomal cytochrome P450 levels in the liver and kidneys, nor the cytochrome P450 content in the renal mitochondria.
