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'.