The effects of carcinogenic heterocyclic amines and -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 -carbolines studied, carcinogenic tryptophan pyrolysis products had greater pharmacological activities than other heterocyclic amines. The carcinogenic tryptophan pyrolysis products, 3-amino-l,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-l-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 IC 50 (the concentrations causing 50% inhibition) values of 10 μιηοΐ/ΐ and 50 μιηοΐ/ΐ, respectively. 3-Amino-l,4-dimethyl-5H-pyrido[4,3-b]indoleand 3-amino-l-methyl-5H-pyrido[4,3-b]indole by themselves did not induce platelet aggregation, although these dietary carcinogens structurally resemble 54iydroxytryptamine. Kinetic analyses showed that 3-amino-l,4-dimethyl-5H-pyrido [4,3^b]indole and 3*amino-l-methyl-5H-pyrido[4,3-b]indole were potent competitive inhibitors of 5-hydroxytryptamine uptake by platelets with /ζ 18 μπιοΐ/ΐ and 42 μιηοΐ/ΐ, respectively. Furthermore, carcinogenic tryptophan pyrolysates as well as -carbolines were found to be competitive selective inhibitors of monoamine oxidase 'type A'.
IntroductionAmong such carcinogens, 3-amino-l ,4-dimethyl-5H-During the last decade, a new series of heterocyclic pyrido[4,3-b]indole, 3-amino-l-methyl-5H-pyramines has been isolated as potent mutagens from ido[4,3-b]indole and γ-carboline derivatives, strongly pyrolysates of amino acids and proteins and from inhibit human platelet aggregation by inhibiting prosbroiled fish and meat (1, 2). All the mutagenic het-taglandin endoperoxide synthetase (7). In the course erocyclic amines so far tested have been shown to be of the previous study, we found that 3-amino-l,4-carcinogenic in experimental animals (1,2). Recently, dimethyl-5H-pyrido[4,3-b]indole and 3-amino-lsome mutagenic and carcinogenic heterocyclic amines methyl-5H-pyrido [4,3-b]indole are also potent inhibsuch as 3,amino-l,4-dimethyl- 5H-pyrido[4,3-b]indole, itors of 5-hydroxytryptamine-induced human platelet 3-amino-l-methyl, 5H-pyrido[4,3-b]indole, 2-amino-aggregation. Since aggregation induced by 5-hydroxyo-methyldipyridoIl^-arS'^'-dlimidazole and 2-ami-tryptamine is mediated by a specific receptor (8,9), nodipyrido[l>a:^2'-d]imidazote were identified in il is perhaps relevant that the tryptophan pyrolysis the dialysis fluid of patients with uraemia, and in products, 3-amino-l,4-dimethyl-5H-pyrido[4,3-b]-human plasma (3-6).indole and 3-amino-l -methyl-5H-pyrido[4,3-b]indole, are structurally related to 5-hydroxytryptamine (ser-