Carcinogenesis, Vol 19, 1995-2000, Copyright © 1998 by Oxford University Press
Y Totsuka, N Hada, K Matsumoto, N Kawahara, Y Murakami, Y Yokoyama, T Sugimura and K Wakabayashi
Norharman (9H-pyrido[3,4-b]indole), widely distributed in our environment,
including cigarette smoke and cooked foodstuffs, is not mutagenic to
Salmonella strains, but becomes mutagenic to S.typhimurium TA98 and YG1024
with S9 mix in the presence of non-mutagenic aromatic amines such as
aniline and o-toluidine. To elucidate the mechanisms of co-mutagenicity, we
tried to isolate the mutagen(s) produced by a reaction between norharman
and aniline with S9 mix. By HPLC purification, two mutagenic compounds (I
and II), one (I) showing mutagenicity with and the other (II) without S9
mix, were isolated. The structure of compound I was deduced to be a coupled
compound of norharman and aniline,
9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman), by a
variety of spectrometry techniques and this was confirmed by its chemical
synthesis. The mutagenic activity of this novel heterocyclic amine was
tested using the pre-incubation method and was found to induce 187,000
revertants in TA98 and 1,783,000 revertants in YG1024 per microg with S9
mix. Compound II was shown to be hydroxyaminophenylnorharman. Formation of
the same DNA adducts was observed in YG1024 when aminophenylnorharman or a
mixture of norharman plus aniline was incubated with S9 mix. The
hydroxyamino derivative also yielded the same DNA adducts in YG1024. Thus,
the appearance of mutagenicity by norharman with aniline in the presence of
S9 mix suggests that the coupled mutagenic compound, aminophenylnorharman,
is formed from norharman and aniline, then converted to the hydroxyamino
derivative and forms DNA adducts to induce mutations in TA98 and YG1024.
ARTICLES
Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan. ytotsuka@gan2.ncc.go.jp
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