Amine-mediated toxicity. The effects of dopamine, norepinephrine, 5-hydroxytryptamine, 6-hydroxydopamine, ascorbate, glutathione and peroxide on the in vitro activities of creatine and adenylate kinases in the brain of the rat.
The effects of several concentrations of amines and reducing agents on the activity of creatine (CK) and adenylate (AK) kinases were determined in homogenates of the brain of the rat at 0 and 37 degrees C. The order of decreasing irreversible inhibition of the enzymes was peroxide, 6-hydroxydopamine, dopamine, norepinephrine, 5-hydroxytryptamine. At 37 degrees C, approx. 50% of the activity of creatine kinase was lost in 30 min in the presence of 20 microM dopamine. 5-Hydroxytryptamine was several orders of magnitude less toxic. The action of dopamine was not prevented by inhibition of monoamine oxidase, chelation of metals or the addition of a catalase, indicating that formation of peroxide by monoamine oxidase was not the primary cause of the loss of enzyme. Although auto-oxidation of dopamine to a toxic quinone was considered, the degree of inhibition of creatine kinase was not affected when auto-oxidation was prevented under anaerobic conditions. Glutathione (GSH), present during the incubation, protected the enzymes but could not restore activity after exposure to amine. Concentrations of glutathione above 5 mM and of oxidized glutathione as low as 10 microM inhibited creatine kinase. Ascorbate protected the enzymes even when present at a concentration much less than that of the amine, but ascorbate was itself toxic. The findings indicate that dopamine, at concentrations attained after drug-induced release or ischemia, can be toxic to a metabolic enzyme present in the synaptosomal membrane.
D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001679:Biogenic Amines / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology*; D003402:Creatine Kinase / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006892:Hydroxydopamines / Q000494:pharmacology; D066298:In Vitro Techniques; D009638:Norepinephrine / Q000494:pharmacology; D016627:Oxidopamine; D010770:Phosphotransferases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000494:pharmacology
D000975:Antioxidants; D001679:Biogenic Amines; D006892:Hydroxydopamines; D012701:Serotonin; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D010770:Phosphotransferases; D003402:Creatine Kinase; D000263:Adenylate Kinase; D005978:Glutathione; D001205:Ascorbic Acid; D004298:Dopamine; D009638:Norepinephrine