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首页> 外文期刊>International Journal of Molecular Sciences >Effects and Mechanism of Nano-Copper Exposure on Hepatic Cytochrome P450 Enzymes in Rats
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Effects and Mechanism of Nano-Copper Exposure on Hepatic Cytochrome P450 Enzymes in Rats

机译：纳米铜暴露对大鼠肝细胞色素P450酶的影响及其机制

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Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals.
机译：尽管目前广泛使用纳米铜，但口服暴露后对肝细胞色素P450（CYP450）酶的不良影响尚不清楚。在这项研究中，我们确定了纳米铜和微铜对大鼠肝脏CYP450酶表达和活性的影响及其作用机理。每天连续7天将大鼠口服微型铜（400 mg / kg），铜离子（100 mg / kg）或纳米铜（100、200和400 mg / kg）。在所有大鼠的肝脏中测量了组织病理学，炎性和氧化应激。测定CYP450酶的mRNA水平和活性，以及​​选择的核受体的mRNA水平。相对于对照，暴露于纳米铜（400 mg / kg）会引起明显的氧化应激和炎症，这由白介素（IL）-2，IL-6，干扰素（IFN）-γ，巨噬细胞炎性蛋白（MIP）的水平升高所表明-1），总抗氧化能力（T-AOC），丙二醛（MDA），诱导型一氧化氮合酶（iNOS）和一氧化氮（NO）。在400 mg / kg纳米铜处理的大鼠中，孕烷X受体（PXR），组成型雄烷烃受体（CAR）和芳烃受体（AHR）的mRNA表达水平显着降低。纳米铜激活了NF-κB（NF-κB），有丝分裂原激活的蛋白激酶（MAPK）以及信号转导和转录激活子（STAT）3信号通路的表达。纳米铜以剂量依赖性方式降低CYP 1A2、2C11、2D6、2E1和3A4的mRNA表达和活性。微量铜对大鼠口服CYP450酶的不良影响不如纳米铜严重。摄入大量的纳米铜会抑制各种CYP450酶的表达，从而严重影响肝脏的药物代谢，从而增加动物体内药物与药物相互作用的风险。

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