Stiborová Marie, Dracínská Helena, Mizerovská Jana, Frei Eva, Schmeiser Heinz H, Hudecek Jirí, Hodek Petr, Phillips David H, Arlt Volker M
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic.
Toxicology. 2008 May 2;247(1):11-22. doi: 10.1016/j.tox.2008.01.018. Epub 2008 Feb 6.
3-Nitrobenzanthrone (3-NBA) is a carcinogen occurring in diesel exhaust and air pollution. Using the (32)P-postlabelling method, we found that 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), are activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney. Each compound generated identical five DNA adducts. We have demonstrated the importance of pulmonary and renal NAD(P)H:quinone oxidoreductase (NQO1) to reduce 3-NBA to species that are further activated by N,O-acetyltransferases and sulfotransferases. Cytochrome P450 (CYP) 1A1 is the essential enzyme for oxidative activation of 3-ABA in microsomes of both organs, while cyclooxygenase plays a minor role. 3-NBA was also investigated for its ability to induce NQO1 and CYP1A1 in lungs and kidneys, and for the influence of such induction on DNA adduct formation by 3-NBA and 3-ABA. When cytosols from rats treated i.p. with 40mg/kg bw of 3-NBA were incubated with 3-NBA, DNA adduct formation was up to 2.1-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. Incubations of 3-ABA with microsomes of 3-NBA-treated rats led to up to a fivefold increase in DNA adduct formation relative to controls. The stimulation of DNA adduct formation correlated with the potential of 3-NBA to induce protein expression and activity of CYP1A1. These results demonstrate that 3-NBA is capable to induce NQO1 and CYP1A1 in lungs and kidney of rats thereby enhancing its own genotoxic and carcinogenic potential.
3-硝基苯并蒽酮（3-NBA）是一种存在于柴油废气和空气污染中的致癌物。使用³²P后标记法，我们发现3-NBA及其人体代谢产物3-氨基苯并蒽酮（3-ABA）可被从大鼠肺（3-NBA致癌作用的靶器官）和肾脏分离出的胞质溶胶和/或微粒体激活，形成DNA加合物的物种。每种化合物都产生了相同的五种DNA加合物。我们已经证明了肺和肾中的NAD(P)H：醌氧化还原酶（NQO1）将3-NBA还原为可被N,O-乙酰基转移酶和磺基转移酶进一步激活的物种的重要性。细胞色素P450（CYP）1A1是两个器官微粒体中3-ABA氧化激活的关键酶，而环氧化酶起次要作用。我们还研究了3-NBA诱导肺和肾中NQO1和CYP1A1的能力，以及这种诱导对3-NBA和3-ABA形成DNA加合物的影响。当用40mg/kg体重的3-NBA腹腔注射处理的大鼠的胞质溶胶与3-NBA一起孵育时，DNA加合物的形成比与对照动物的胞质溶胶孵育时高2.1倍。这种增加与NQO1的蛋白质水平和酶活性的增加相对应。3-ABA与3-NBA处理的大鼠的微粒体孵育导致DNA加合物形成相对于对照增加高达五倍。DNA加合物形成的刺激与3-NBA诱导CYP1A1蛋白质表达和活性的潜力相关。这些结果表明，3-NBA能够在大鼠的肺和肾中诱导NQO1和CYP1A1，从而增强其自身的遗传毒性和致癌潜力。
