Hydrogen peroxide production in mouse tissues after acute d-amphetamine administration. Influence of monoamine oxidase inhibition.
The toxicity of amphetamines is conditioned by a complex array of mechanisms, involving the increase of neurotransmission (e.g. leading to hyperthermia) and enzymatic and non-enzymatic oxidation of amphetamines and biogenic amines. Considering that all these processes may increase the generation of hydrogen peroxide (H2O2) by metabolic or non-metabolic redox pathways, the main objective of this work was to evaluate d-amphetamine-induced H2O2 production in mice liver, kidney and heart. The contribution of monoamine oxidase (MAO) to H2O2 production after d-amphetamine administration was studied using the MAO inhibitor pargyline. H2O2 production was measured indirectly using the catalase-H2O2 complex I irreversible inhibitor 3-amino-1,2,4-triazole (AT). Using this method, the measurement of residual catalase activity following administration of AT permits the monitoring of H2O2 production in vivo. Charles River CD-1 mice (30-35 g body weight) were injected with AT just before the injection of d-amphetamine sulphate (20 mg/kg). d-Amphetamine stimulated the production of H2O2 in all tissues studied, although to different degrees. MAO inhibition by itself led to a remarkable decrease of basal H2O2 production in the kidney and a slight decrease in the liver, although no effect was observed in the heart. d-Amphetamine-induced H2O2 production in the heart and kidney was reduced in MAO-inhibited mice. However, in the liver, H2O2 production was transiently potentiated at 30 min under MAO inhibition. In conclusion, d-amphetamine administration leads to an increase in H2O2 production in mouse liver, kidney and heart, and monoamine oxidase plays an important role in this effect.
Carvalho
F
F
ICETA/CEQUP, Toxicology Department, Faculty of Pharmacy, University of Porto, Portugal. felixdc@ff.up.pt
Duarte
J A
JA
Neuparth
M J
MJ
Carmo
H
H
Fernandes
E
E
Remião
F
F
Bastos
M L
ML
D000818:Animals; D003913:Dextroamphetamine / Q000633:toxicity*; D006321:Heart / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000032:analysis*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008995:Monoamine Oxidase / Q000096:biosynthesis*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D023382:Toxicity Tests, Acute
D008996:Monoamine Oxidase Inhibitors; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D003913:Dextroamphetamine