Reshetnikova Galina, Sidorenko Viktoriya S, Whyard Terry, Lukin Mark, Waltzer Wayne, Takamura-Enye Takeji, Romanov Victor
Department of Urology, SUNY at Stony Brook, 11794, USA.
Department of Pharmacological Sciences, SUNY at Stony Brook, 11794, USA.
Exp Cell Res. 2016 Nov 15;349(1):101-108. doi: 10.1016/j.yexcr.2016.10.003. Epub 2016 Oct 5.
3-Nitrobenzanthrone (3-NBA), a potential human carcinogen, is present in diesel exhaust. The main metabolite of 3-NBA, 3-aminobenzanthrone, was detected in urine of miners occupationally exposed to diesel emissions. Environmental and occupational factors play an important role in development of bladder cancer (BC), one of the most frequent malignancies. It is expected that exposure of urothelium to 3-NBA and its metabolites may induce BC initiation and/or progression. To test this hypothesis, we studied geno- and cytotoxicity of 3-NBA using an in vitro BC model. 3-NBA induced higher levels of DNA adducts, reactive oxygen species and DNA breaks in aggressive T24 cells than in more differentiated RT4 cells. To understand the nature of this difference we examined the role of several enzymes that were identified as 3-NBA bio activators. However, the difference in DNA adduct formation cannot be directly linked to the different activity of any of the examined enzymes. Conversely, the difference of tested cell lines in p53 status can partly explain the distinct levels of 3-NBA-DNA adducts and DNA damage induced by 3-NBA. Therefore, we assume that more aggressive T24 cells are more predisposed for DNA adduct formation, DNA damage and, possibly, mutations and as a result further tumorigenesis.
3-硝基苯并蒽酮（3-NBA）是一种潜在的人类致癌物，存在于柴油尾气中。在职业接触柴油排放物的矿工尿液中检测到了3-NBA的主要代谢产物3-氨基苯并蒽酮。环境和职业因素在膀胱癌（BC）的发生发展中起着重要作用，膀胱癌是最常见的恶性肿瘤之一。预计尿路上皮暴露于3-NBA及其代谢产物可能会诱发膀胱癌的起始和/或进展。为了验证这一假设，我们使用体外膀胱癌模型研究了3-NBA的基因毒性和细胞毒性。与分化程度更高的RT4细胞相比，3-NBA在侵袭性T24细胞中诱导产生更高水平的DNA加合物、活性氧物种和DNA断裂。为了了解这种差异的本质，我们研究了几种被鉴定为3-NBA生物激活剂的酶的作用。然而，DNA加合物形成的差异不能直接与任何一种被检测酶的不同活性联系起来。相反，受试细胞系在p53状态上的差异可以部分解释3-NBA诱导的3-NBA-DNA加合物和DNA损伤的不同水平。因此，我们假设更具侵袭性的T24细胞更容易形成DNA加合物、遭受DNA损伤，可能还会发生突变，进而导致进一步的肿瘤发生。
