Toxicity of Pb2+ on rat liver mitochondria induced by oxidative stress and mitochondrial permeability transition,Toxicology Research

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Toxicity of Pb2+ on rat liver mitochondria induced by oxidative stress and mitochondrial permeability transition
Toxicology Research ( IF 2.2 ) Pub Date : 2017-09-25 00:00:00 , DOI: 10.1039/c7tx00204a
Long Ma _{1,

2,

3,

4,

5} , Jun-Yi Liu _{6,

7,

8} , Jia-Xin Dong _{5,

9,

10,

11,

12} , Qi Xiao _{5,

13,

14,

15} , Jie Zhao _{1,

2,

3,

4,

5} , Feng-Lei Jiang _{1,

2,

3,

4,

5}

Affiliation

State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE)
College of Chemistry and Molecular Sciences
Wuhan University
Wuhan 430072
P. R. China
The Bryn Mawr School
Baltimore
USA
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources
School of Chemistry and Pharmaceutical Sciences
Guangxi Normal University
Guilin 541004
College of Chemistry and Material Science
Guangxi Teachers Education University
Nanning 530001

Pb²⁺ exposure in humans occurs mainly through air inhalation, food and water uptake which has been shown to be generally associated with numerous body functions such as the central and peripheral nervous systems, the red blood cells, the kidneys and the liver. It has been reported that the liver is the storage site and an important primary target in Pb²⁺ toxicity, and the hepatotoxicity of Pb²⁺ could be resulted from the impairment of the liver mitochondria. In this study, several mitochondrial dysfunctions following the addition of Pb²⁺ (10–160 μM) were investigated. We found that Pb²⁺ inhibited the enzyme activities of mitochondrial respiratory complexes and complex III was the major source of Pb²⁺-induced significant reactive oxygen species (ROS) formation. As a consequence, our results showed that Pb²⁺ induced significant progress in mitochondrial lipid peroxidation, adenosine triphosphate (ATP) consumption and glutathione (GSH) oxidation. On the other hand, Pb²⁺ induced marked changes in mitochondrial permeability transition (MPT) accompanied by mitochondrial swelling, mitochondrial membrane potential collapse, mitochondrial membrane fluidity decrease and cytochrome c (Cyt c) release. Additionally, several mitochondrial MPT inhibitors and chelators were utilized to determine the possible interaction sites of Pb²⁺ on mitochondria. In general, our data supported that the Pb²⁺-induced liver toxicity was a result of the disruptive effect on the mitochondrial respiratory complexes. This disruptive effect caused oxidative stress and MPT, which led to mitochondrial dysfunctions and even cell death signalling via mitochondrial permeability transition pore (MPTP) opening and Cyt c release.

中文翻译：

氧化应激和线粒体通透性转变诱导的Pb ²⁺对大鼠肝线粒体的毒性

人体中Pb ^2+的暴露主要是通过空气吸入，食物和水摄入而发生的，这已被证明通常与许多身体功能有关，例如中枢和周围神经系统，红细胞，肾脏和肝脏。据报道，肝脏是储存场地和铅的重要首要目标²⁺毒性，和铅的肝毒性²⁺可从肝线粒体的减值所致。在这项研究中，研究了添加Pb ²⁺（10–160μM）后的几种线粒体功能障碍。我们发现Pb ²⁺抑制线粒体呼吸复合物的酶活性，而复合物III是Pb的主要来源²⁺诱导显着的活性氧（ROS）形成。结果，我们的结果表明，Pb²⁺在线粒体脂质过氧化，三磷酸腺苷（ATP）消耗和谷胱甘肽（GSH）氧化方面诱导了重大进展。另一方面，Pb²⁺引起线粒体通透性转变（MPT）的显着变化，伴随着线粒体肿胀，线粒体膜电位塌陷，线粒体膜流动性降低和细胞色素c（Cyt c）释放。另外，利用几种线粒体MPT抑制剂和螯合剂来确定线粒体上Pb²⁺的可能相互作用位点。总的来说，我们的数据支持铅²⁺诱导的肝毒性是对线粒体呼吸复合物的破坏作用的结果。这种破坏性作用导致氧化应激和MPT，从而导致线粒体功能障碍，甚至通过线粒体通透性转换孔（MPTP）打开和Cyt c释放而导致细胞死亡。

更新日期：2017-10-30

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