Vinken Mathieu, Doktorova Tatyana, Decrock Elke, Leybaert Luc, Vanhaecke Tamara, Rogiers Vera
Department of Toxicology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
Crit Rev Biochem Mol Biol. 2009 Jul-Aug;44(4):201-22. doi: 10.1080/10409230903061215.
Direct communication between hepatocytes, mediated by gap junctions, constitutes a major regulatory platform in the control of liver homeostasis, ranging from hepatocellular proliferation to hepatocyte cell death. Inherent to this pivotal task, gap junction functionality is frequently disrupted upon impairment of the homeostatic balance, as occurs during liver toxicity and carcinogenicity. In the present paper, the deleterious effects of a number of chemical and biological toxic compounds on hepatic gap junctions are discussed, including environmental pollutants, biological toxins, organic solvents, pesticides, pharmaceuticals, peroxides, metals and phthalates. Particular attention is paid to the molecular mechanisms that underlie the abrogation of gap junction functionality. Since hepatic gap junctions are specifically targeted by tumor promoters and epigenetic carcinogens, both in vivo and in vitro, inhibition of gap junction functionality is considered as a suitable indicator for the detection of nongenotoxic hepatocarcinogenicity.
由缝隙连接介导的肝细胞间直接通讯构成了肝脏稳态控制中的一个主要调节平台，其范围涵盖从肝细胞增殖到肝细胞死亡。对于这一关键任务而言，缝隙连接功能在稳态平衡受损时（如在肝脏毒性和致癌过程中发生的情况）常常遭到破坏。在本文中，讨论了多种化学和生物毒性化合物对肝脏缝隙连接的有害影响，包括环境污染物、生物毒素、有机溶剂、农药、药物、过氧化物、金属和邻苯二甲酸盐。特别关注了导致缝隙连接功能丧失的分子机制。由于肝脏缝隙连接在体内和体外均是肿瘤启动子和表观遗传致癌物的特定作用靶点，因此缝隙连接功能的抑制被视为检测非遗传毒性肝癌发生的一个合适指标。
