TY - JOUR
T1 - Metabolic Activation of 1-Methyl-3-amino-5H-pyrido[4,3-b]indole and Several Structurally Related Mutagens
AU - Pezzuto, John M.
AU - Moore, Patrick D.
AU - Hecht, Sidney M.
PY - 1981/1
Y1 - 1981/1
N2 - It has recently been reported that the pyrolysis of tryptophan results in the production of 1-methyl-3-amino-5H-pyrido[4,3-b]indole (1) and 1,3-dimethyl-3-amino-5H-pyrido [4,3-0] 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 barman 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.
AB - It has recently been reported that the pyrolysis of tryptophan results in the production of 1-methyl-3-amino-5H-pyrido[4,3-b]indole (1) and 1,3-dimethyl-3-amino-5H-pyrido [4,3-0] 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 barman 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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U2 - 10.1021/bi00505a011
DO - 10.1021/bi00505a011
M3 - Article
C2 - 7008841
AN - SCOPUS:0019515488
SN - 0006-2960
VL - 20
SP - 298
EP - 305
JO - Biochemistry
JF - Biochemistry
IS - 2
ER -