Xie Yaxiong, Liu Jie, Liu Yaping, Klaassen Curtis D, Waalkes Michael P
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Mol Cell Biochem. 2004 Jan;255(1-2):11-8. doi: 10.1023/b:mcbi.0000007256.44450.8c.
Multidrug-resistance gene knockout mdr1a/1b(-/-) mice, which are deficient in P-glycoproteins, are more sensitive than wild-type (WT) mice to acute arsenic toxicity. This study assessed toxic manifestations of chronic oral arsenic in mdr1a/1b(-/-) mice, including oxidative stress and altered gene expression, and investigated altered toxicokinetics as a potential basis of enhanced arsenic toxicity. Thus, mdr1a/1b(-/-) and WT mice were exposed to sodium arsenite (0-80 ppm as arsenic) in the drinking water for 10 weeks at which time hepatic arsenic accumulation, lipid peroxidation (LPO), redox status and change in gene expression level were assessed. All mice survived the arsenic exposure, but body weight gain in the highest dose group was reduced in both mdr1a/1b(-/-) and WT mice. Arsenic induced pathological changes, elevated LPO levels and enhanced glutathione S-transferase (GST) activity, in the liver to a greater extent in mdr1a/1b(-/-) than in WT mice. Arsenic also decreased Cu/Zn superoxide dismutase activity in both mdr1a/1b(-/-) and WT mice. The expressions of certain genes, such as those encoding cell proliferation, GST, acute-phase proteins and metabolic enzymes, were modestly altered in arsenic-exposed mice. The expression of cyclin D1, a potential hepatic oncogene, was enhanced in arsenic-exposed mdr1a/1b(-/-) mice only. At the highest level of exposure, hepatic arsenic content was higher in mdr1a/1b(-/-) than in WT mice, suggesting that enhanced accumulation due to transport deficiency may, in part, account for the enhanced toxicity in these mice. In summary, this study shows that chronic arsenic toxicity, including liver pathology and oxidative stress, is enhanced in mdr1a/1b(-/-) mice, possibly due to enhanced accumulation of arsenic as a result of transport system deficiency.
多药耐药基因敲除的mdr1a/1b(-/-)小鼠缺乏P-糖蛋白，对急性砷中毒比野生型（WT）小鼠更敏感。本研究评估了mdr1a/1b(-/-)小鼠慢性口服砷的毒性表现，包括氧化应激和基因表达改变，并研究了毒代动力学改变作为砷毒性增强的潜在基础。因此，将mdr1a/1b(-/-)和WT小鼠暴露于饮用水中的亚砷酸钠（砷含量为0-80 ppm）10周，此时评估肝脏砷蓄积、脂质过氧化（LPO）、氧化还原状态和基因表达水平变化。所有小鼠在砷暴露后均存活，但最高剂量组的mdr1a/1b(-/-)和WT小鼠体重增加均减少。砷诱导的肝脏病理变化、LPO水平升高和谷胱甘肽S-转移酶（GST）活性增强，在mdr1a/1b(-/-)小鼠中比WT小鼠更明显。砷还降低了mdr1a/1b(-/-)和WT小鼠的铜/锌超氧化物歧化酶活性。某些基因的表达，如编码细胞增殖、GST、急性期蛋白和代谢酶的基因，在砷暴露小鼠中略有改变。仅在砷暴露的mdr1a/1b(-/-)小鼠中，潜在的肝脏癌基因细胞周期蛋白D1的表达增强。在最高暴露水平下，mdr1a/1b(-/-)小鼠肝脏中的砷含量高于WT小鼠，这表明由于转运缺陷导致的蓄积增加可能部分解释了这些小鼠毒性增强的原因。总之，本研究表明，mdr1a/1b(-/-)小鼠的慢性砷毒性，包括肝脏病理和氧化应激，有所增强，可能是由于转运系统缺陷导致砷蓄积增加所致。
