Metabolic activation of 1-methyl-3-amino-5H-pyrido[4,3-6]indole and several structurally related mutagens

John M. Pezzuto, Patrick D. Moore, Sidney Hecht

Research output: Contribution to journalArticle

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Abstract

It has recently been reported that the pyrolysis of tryptophan results in the production of 1-methyl-3-amino-5H-pyrido[4,3-6]indole (1) and 1,3-dimethyl-3-amino-5H-pyrido[4,3-b]indole (2), which are potent frame-shift mutagens. The covalent binding of these compounds to deoxyribonucleic acid (DNA) in the presence of rat liver microsomes and reduced nicotinamide adenine dinucleotide phosphate is demonstrated. In addition to 1 and 2, we have synthesized the N3-acetyl (3), N3-ethyl (4), N3,N3-diethyl (5), 3-hydroxy (6), 7-methyl (7), and 8-methyl (8) derivatives of 1 for utilization in a forward-mutation assay employing Salmonella typhimurium strain TM677. The mutagenic activity of the compounds was found to follow the order 1 > 2 > 4 ≥ 5 ≥ 7 > 8 > 3 > 6. Metabolic activation was necessary to convert the compounds to active mutagens, and the required activity was found to be localized in the liver microsomal fraction of 3-methylcholanthrene-induced rats. The reduced mutagenic activity of 3 and the inactivity of 6, carbazole, norharman, and harman suggest oxidation of the aminopyridine portion of 1 in its activation. The reduced activity of 7 and 8, and the remaining activity of 4 and 5, may be due to factors such as less efficient physicochemical interaction with the bacterial DNA, although additional metabolic sites of activation of compound 1 are also possible. Microsomes isolated from phenobarbital-pretreated rats were much less effective for the activation of 1 or 3, whereas 2-aminofluorene (a compound having mutagenic potential similar to that of 3) or 2-acetylaminofluorene (AAF) was activated equally as well with either preparation of microsomes. Additionally, benzoflavone and norharman were shown to inhibit the mutagenic response obtained with 1, in contrast to AAF which demonstrated higher mutagenic activity in the presence of these compounds. Since AAF is known to require N-oxidation for the expression of mutagenicity, the data suggest alternate sites of metabolic activation and detoxification for 1 and AAF which can be differentiated. Structural dissimilarities may result in highly efficacious metabolic activation of 1 to mutagenic species.

Original languageEnglish (US)
Pages (from-to)298-305
Number of pages8
JournalBiochemistry
Volume20
Issue number2
StatePublished - 1981
Externally publishedYes

Fingerprint

2-Acetylaminofluorene
norharman
Mutagens
Chemical activation
Microsomes
Rats
Benzoflavones
Aminopyridines
Liver
Methylcholanthrene
DNA
Liver Microsomes
Salmonella typhimurium
Phenobarbital
NADP
Tryptophan
Oxidation
Detoxification
Salmonella
Mutation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Metabolic activation of 1-methyl-3-amino-5H-pyrido[4,3-6]indole and several structurally related mutagens. / Pezzuto, John M.; Moore, Patrick D.; Hecht, Sidney.

In: Biochemistry, Vol. 20, No. 2, 1981, p. 298-305.

Research output: Contribution to journalArticle

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abstract = "It has recently been reported that the pyrolysis of tryptophan results in the production of 1-methyl-3-amino-5H-pyrido[4,3-6]indole (1) and 1,3-dimethyl-3-amino-5H-pyrido[4,3-b]indole (2), which are potent frame-shift mutagens. The covalent binding of these compounds to deoxyribonucleic acid (DNA) in the presence of rat liver microsomes and reduced nicotinamide adenine dinucleotide phosphate is demonstrated. In addition to 1 and 2, we have synthesized the N3-acetyl (3), N3-ethyl (4), N3,N3-diethyl (5), 3-hydroxy (6), 7-methyl (7), and 8-methyl (8) derivatives of 1 for utilization in a forward-mutation assay employing Salmonella typhimurium strain TM677. The mutagenic activity of the compounds was found to follow the order 1 > 2 > 4 ≥ 5 ≥ 7 > 8 > 3 > 6. Metabolic activation was necessary to convert the compounds to active mutagens, and the required activity was found to be localized in the liver microsomal fraction of 3-methylcholanthrene-induced rats. The reduced mutagenic activity of 3 and the inactivity of 6, carbazole, norharman, and harman suggest oxidation of the aminopyridine portion of 1 in its activation. The reduced activity of 7 and 8, and the remaining activity of 4 and 5, may be due to factors such as less efficient physicochemical interaction with the bacterial DNA, although additional metabolic sites of activation of compound 1 are also possible. Microsomes isolated from phenobarbital-pretreated rats were much less effective for the activation of 1 or 3, whereas 2-aminofluorene (a compound having mutagenic potential similar to that of 3) or 2-acetylaminofluorene (AAF) was activated equally as well with either preparation of microsomes. Additionally, benzoflavone and norharman were shown to inhibit the mutagenic response obtained with 1, in contrast to AAF which demonstrated higher mutagenic activity in the presence of these compounds. Since AAF is known to require N-oxidation for the expression of mutagenicity, the data suggest alternate sites of metabolic activation and detoxification for 1 and AAF which can be differentiated. Structural dissimilarities may result in highly efficacious metabolic activation of 1 to mutagenic species.",
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