Effect of 10-aza-substitution on benzo[a]pyrene mutagenicity in vivo and in vitro.
Benzo[a]pyrene (BaP), an environmental carcinogen, shows genotoxicity after metabolic transformation into the bay-region diol epoxide, BaP-7,8-diol 9,10-epoxide. 10-Azabenzo[a]pyrene (10-azaBaP), in which a ring nitrogen is located in the bay-region, is also a carcinogen and shows mutagenicity in the Ames test in the presence of the rat liver microsomal enzymes. In order to evaluate the effect of aza-substitution on in vivo genotoxicity, BaP and 10-azaBaP were assayed for their in vivo mutagenicity using the lacZ-transgenic mouse (MutaMouse). BaP was potently mutagenic in all of the organs examined (liver, lung, kidney, spleen, forestomach, stomach, colon, and bone marrow), as described in our previous report, whereas, 10-azaBaP was slightly mutagenic only in the liver and colon. The in vitro mutagenicities of BaP and 10-azaBaP were evaluated by the Ames test using liver homogenates prepared from several sources, i.e. CYP1A-inducer-treated rats, CYP1A-inducer-treated and non-treated mice, and humans. BaP showed greater mutagenicities than 10-azaBaP in the presence of a liver homogenate prepared from CYP1A-inducer-treated rodents. However, 10-azaBaP showed mutagenicities similar to or more potent than BaP in the presence of a liver homogenate or S9 from non-treated mice and humans. These results indicate that 10-aza-substitution markedly modifies the nature of mutagenicity of benzo[a]pyrene in both in vivo and in vitro mutagenesis assays.
Yamada
Katsuya
K
Faculty of Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Mizuho-ku, Nagoya 467-8603, Japan.
Suzuki
Takayoshi
T
Kohara
Arihiro
A
Hayashi
Makoto
M
Hakura
Atsushi
A
Mizutani
Takaharu
T
Saeki
Ken-ichi
K
D000818:Animals; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000737:chemistry* / Q000633:toxicity*; D001580:Benzopyrenes / Q000737:chemistry / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D009154:Mutation; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D001580:Benzopyrenes; D009153:Mutagens; C023961:10-azabenzo(a)pyrene; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1