Yamada Katsuya, Suzuki Takayoshi, Kohara Arihiro, Hayashi Makoto, Hakura Atsushi, Mizutani Takaharu, Saeki Ken-ichi
Faculty of Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Mizuho-ku, Nagoya 467-8603, Japan.
Mutat Res. 2002 Nov 26;521(1-2):187-200. doi: 10.1016/s1383-5718(02)00240-1.
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.
苯并[a]芘（BaP）是一种环境致癌物，经代谢转化为湾区二醇环氧化物——苯并[a]芘-7,8-二醇-9,10-环氧化物后具有遗传毒性。10-氮杂苯并[a]芘（10-azaBaP），其中一个环氮位于湾区，也是一种致癌物，在大鼠肝微粒体酶存在的情况下，在艾姆斯试验中表现出致突变性。为了评估氮杂取代对体内遗传毒性的影响，使用lacZ转基因小鼠（MutaMouse）检测了BaP和10-azaBaP的体内致突变性。如我们之前的报告所述，BaP在所有检测的器官（肝脏、肺、肾脏、脾脏、前胃、胃、结肠和骨髓）中都具有很强的致突变性，而10-azaBaP仅在肝脏和结肠中具有轻微的致突变性。使用从多种来源制备的肝脏匀浆，即经CYP1A诱导剂处理的大鼠、经CYP1A诱导剂处理和未处理的小鼠以及人类，通过艾姆斯试验评估了BaP和10-azaBaP的体外致突变性。在由经CYP1A诱导剂处理的啮齿动物制备的肝脏匀浆存在的情况下BaP显示出比10-azaBaP更强的致突变性。然而，在由未处理的小鼠和人类制备的肝脏匀浆或S9存在的情况下，10-azaBaP显示出与BaP相似或更强的致突变性。这些结果表明，在体内和体外诱变试验中，10-氮杂取代显著改变了苯并[a]芘的致突变性。
