Suzuki Shugo, Arnold Lora L, Pennington Karen L, Kakiuchi-Kiyota Satoko, Cohen Samuel M
Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA.
Toxicology. 2009 Jun 30;261(1-2):41-6. doi: 10.1016/j.tox.2009.04.042. Epub 2009 May 3.
Arsenite (As(III)), an inorganic arsenical, is a known human carcinogen, inducing tumors of the skin, urinary bladder and lung. It is metabolized to organic methylated arsenicals. Oxidative stress has been suggested as a mechanism for arsenic-induced carcinogenesis. Reactive oxygen species (ROS) can be important factors for carcinogenesis and tumor progression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is known to produce intracellular ROS, therefore, we investigated the ability of apocynin (acetovanillone), an NADPH oxidase inhibitor, to inhibit the cytotoxicity and regenerative cell proliferation of arsenic in vitro and in vivo. Apocynin had similar effects in reducing the cytotoxicity of As(III) and dimethylarsinous acid (DMA(III)) in rat urothelial cells in vitro. When tested at the same concentrations as apocynin, other antioxidants, such as l-ascorbate and N-acetylcysteine, did not inhibit As(III)-induced cytotoxicity but they were more effective at inhibiting DMA(III)-induced cytotoxicity compared with apocynin. In vivo, female rats were treated for 3 weeks with 100ppm As(III). Immunohistochemical staining for 8-hydroxy-2'-deoxyguanosine (8-OHdG) showed that apocynin reduced oxidative stress partially induced by As(III) treatment on rat urothelium, and significantly reduced the cytotoxicity of superficial cells detected by scanning electron microscopy (SEM). However, based on the incidence of simple hyperplasia and the bromodeoxyuridine (BrdU) labeling index, apocynin did not inhibit As(III)-induced urothelial cell proliferation. These data suggest that the NADPH oxidase inhibitor, apocynin, may have the ability to partially inhibit arsenic-induced oxidative stress and cytotoxicity of the rat bladder epithelium in vitro and in vivo. However, apocynin did not inhibit the regenerative cell proliferation induced by arsenite in a short-term study.
亚砷酸盐（As(III)），一种无机砷化合物，是已知的人类致癌物，可诱发皮肤、膀胱和肺部肿瘤。它会代谢为有机甲基化砷化合物。氧化应激被认为是砷诱导致癌的一种机制。活性氧（ROS）可能是致癌和肿瘤进展的重要因素。已知烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶可产生细胞内ROS，因此，我们研究了NADPH氧化酶抑制剂阿朴吗啡（乙酰香草酮）在体外和体内抑制砷的细胞毒性和再生细胞增殖的能力。阿朴吗啡在体外对降低大鼠尿路上皮细胞中As(III)和二甲基亚砷酸（DMA(III)）的细胞毒性具有相似的作用。当以与阿朴吗啡相同的浓度进行测试时，其他抗氧化剂，如L-抗坏血酸和N-乙酰半胱氨酸，并未抑制As(III)诱导的细胞毒性，但与阿朴吗啡相比，它们在抑制DMA(III)诱导的细胞毒性方面更有效。在体内，雌性大鼠用100ppm的As(III)处理3周。对8-羟基-2'-脱氧鸟苷（8-OHdG）进行免疫组织化学染色显示，阿朴吗啡可部分减轻As(III)处理对大鼠尿路上皮诱导的氧化应激，并显著降低通过扫描电子显微镜（SEM）检测到的表层细胞的细胞毒性。然而，基于单纯增生的发生率和溴脱氧尿苷（BrdU）标记指数，阿朴吗啡并未抑制As(III)诱导的尿路上皮细胞增殖。这些数据表明，NADPH氧化酶抑制剂阿朴吗啡在体外和体内可能具有部分抑制砷诱导的大鼠膀胱上皮氧化应激和细胞毒性的能力。然而，在一项短期研究中，阿朴吗啡并未抑制亚砷酸盐诱导的再生细胞增殖。
