Carcinogenic tryptophan pyrolysis products potent inhibitors of type A monoamine oxidase and the platelet response to 5-hydroxytryptamine.
The effects of carcinogenic heterocyclic amines and beta-carbolines on 5-hydroxytryptamine-induced human platelet aggregation, on the uptake of 5-hydroxytryptamine by platelets, and on human monoamine oxidase activity were investigated. Of the dietary carcinogens and beta-carbolines studied, carcinogenic tryptophan pyrolysis products had greater pharmacological activities than other heterocyclic amines. The carcinogenic tryptophan pyrolysis products, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, which have been identified in the dialysis fluid of uraemic patients, were the most potent inhibitors of the aggregation response to 5-hydroxytryptamine, with IC50 (the concentrations causing 50% inhibition) values of 10 mumol/l and 50 mumol/l, respectively. 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole by themselves did not induce platelet aggregation, although these dietary carcinogens structurally resemble 5-hydroxytryptamine. Kinetic analyses showed that 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole were potent competitive inhibitors of 5-hydroxytryptamine uptake by platelets with Ki 18 mumol/l and 42 mumol/l, respectively. Furthermore, carcinogenic tryptophan pyrolysates as well as beta-carbolines were found to be competitive selective inhibitors of monoamine oxidase 'type A'.
Manabe
S
S
Department of Hygiene & Preventive Medicine, Faculty of Medicine, University of Tokyo, Japan.
Kanai
Y
Y
Ishikawa
S
S
Wada
O
O
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D006801:Humans; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009153:Mutagens / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D014364:Tryptophan / Q000378:metabolism / Q000494:pharmacology*
D002243:Carbolines; D002273:Carcinogens; D008996:Monoamine Oxidase Inhibitors; D009153:Mutagens; D012701:Serotonin; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D014364:Tryptophan; D008995:Monoamine Oxidase; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole