Microsomal metabolism and activation of the environmental carcinogen 2-amino-3-methyl-9H-pyrido[23-b]indole.
2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) is a mutagenic and carcinogenic heterocyclic amine formed as a pyrolysis product during cooking of food and combustion of tobacco. Hepatic microsomes from PCB-induced rats metabolized MeA alpha C to four products, of which three were non-mutagenic and one was mutagenic without S9 activation. The three non-mutagenic products, which accounted for 83% of the metabolism of MeA alpha C, were characterized by mass spectrometry and NMR spectroscopy as 6-hydroxy-MeA alpha C, 7-hydroxy-MeA alpha C and 3-hydroxy-methyl-A alpha C. The mutagenic metabolite, accounting for 17% of the metabolism of MeA alpha C, was characterized as N2-hydroxy-MeA alpha C by comparison with the HPLC retention time and UV spectrum of N2-hydroxy-MeA alpha C obtained by chemical synthesis. N2-Hydroxy-MeA alpha C was very reactive and a part of it bound covalently to microsomal proteins during incubation and a part was degraded to other products during incubation or chromatography. N2-Hydroxy-MeA alpha C was mutagenic in Salmonella typhimurium TA98 without metabolic activation, resulting in 5070 revertants/microgram, which was > 20 times the specific mutagenic activity of the parent compound.
Frandsen
H
H
Institute of Toxicology, National Food Agency, Søborg, Denmark. hf@1st.min.dk
Damkjaer
S
S
Grivas
S
S
Andersson
R
R
Binderup
M L
ML
Larsen
J C
JC
D000818:Animals; D001711:Biotransformation / Q000235:genetics; D002243:Carbolines / Q000378:metabolism*; D002274:Carcinogens, Environmental / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000235:genetics
D002243:Carbolines; D002274:Carcinogens, Environmental; D009153:Mutagens; C017821:2-amino-3-methyl-9H-pyrido(2,3-b)indole