Cirovic Ana, Satarug Soisungwan, Jevtic Jovan, Ivanovski Ana, Orisakwe Orish E, Jankovic Sasa, Cirovic Aleksandar
Faculty of Medicine, Institute of Anatomy, University of Belgrade, Dr Subotica 4/2, Belgrade 11000, Serbia.
Kidney Disease Research Collaborative, Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia.
J Trace Elem Med Biol. 2024 Dec;86:127542. doi: 10.1016/j.jtemb.2024.127542. Epub 2024 Oct 6.
The mechanism of hepatocyte destruction in chronic hepatitis is not completely understood, while renal failure in individuals with advanced cirrhosis is a significant concern. It is well known that smokers who are chronically infected with hepatitis B and C viruses (HBV, HCV) have a poor prognosis. In the present review, we propose a novel hypothesis that environmental exposure to a nephrotoxic metal pollutant, cadmium (Cd) may contribute to hepatocyte destruction and, subsequently, affect the duration of chronic hepatitis. The metal binding protein, metallothionein (MT) sequesters cadmium as CdMT complexes, and effectively neutralize its adverse effects. Cadmium can cause the damage to hepatocytes, only when it is in an unbound form. In addition to its ability to bind cadmium, MT can act as a scavenger of reactive oxygen species (ROS). However, the cellular MT levels may decrease, when ROS is excessively produced under the pathologic chronic viral hepatitis conditions, especially while the cellular levels of zinc may also be low. Zinc is an endogenous inducer of MT, and is required for maximal MT expression. High ROS levels in the hepatocytes diminishes MT binding to metals. Consequently, the proportion of unbound Cd is increased and thus there is more hepatic damage. Hepatic damage leads to a copious release of CdMT into the circulation. This significant cadmium load, which occurs after hepatic damage, and in some cases, muscle atrophy, induces kidney damage with resultant renal failure in advanced cirrhosis.
慢性肝炎中肝细胞破坏的机制尚未完全明确，而晚期肝硬化患者的肾衰竭是一个重大问题。众所周知，慢性感染乙型和丙型肝炎病毒（HBV、HCV）的吸烟者预后较差。在本综述中，我们提出了一个新的假说，即环境暴露于肾毒性金属污染物镉（Cd）可能导致肝细胞破坏，进而影响慢性肝炎的病程。金属结合蛋白金属硫蛋白（MT）将镉螯合为CdMT复合物，并有效中和其不良影响。只有当镉处于未结合状态时，它才会对肝细胞造成损害。除了结合镉的能力外，MT还可以作为活性氧（ROS）的清除剂。然而，在病理性慢性病毒性肝炎条件下，尤其是当细胞内锌水平也较低时，ROS过度产生可能会导致细胞内MT水平降低。锌是MT的内源性诱导剂，是MT最大表达所必需的。肝细胞中高ROS水平会减少MT与金属的结合。因此，未结合的Cd比例增加，从而导致更多的肝损伤。肝损伤导致大量CdMT释放到循环中。这种在肝损伤后出现的大量镉负荷，在某些情况下还伴有肌肉萎缩，会导致肾脏损伤，进而在晚期肝硬化中引发肾衰竭。
