Kindrat Iryna, Dreval Kostiantyn, Shpyleva Svitlana, Tryndyak Volodymyr, de Conti Aline, Mudalige Thilak K, Chen Tao, Erstenyuk Anna M, Beland Frederick A, Pogribny Igor P
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, United States; Department of Biological and Medical Chemistry, Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine.
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, United States.
Toxicol Lett. 2017 Nov 5;281:65-73. doi: 10.1016/j.toxlet.2017.09.011. Epub 2017 Sep 19.
The liver, a central detoxification organ and main regulator of systemic iron homeostasis, is prone to damage by xenobiotics. In the present study, we investigated the effect of the hepatotoxicant and hepatocarcinogen methapyrilene hydrochloride on iron metabolism in rat liver in a repeat-dose in vivo toxicity study and in human HepaRG cells in vitro. Treatment of male Fischer 344 (F344) rats with methapyrilene at doses 40 and 80mg/kg body weight (bw)/day by gavage for 6 weeks resulted in changes in the expression of classic hepatotoxicity-related marker genes and iron homeostasis-related genes, especially a prominent, dose-dependent down-regulation of the transferrin (Tf) gene and an up-regulation of the ferritin, light chain (Ftl) gene. A decrease in the level of TF and an increase in the level of FTL also occurred in methapyrilene-treated differentiated HepaRG cells, indicating the existence of interspecies and in vitro-in vivo similarities in the disturbance of cellular iron homeostasis upon liver injury. In contrast, there was minimal overlap in the expression of liver toxicity-marker genes in the livers of rats and in HepaRG cells treated with methapyrilene. Importantly, the decrease of transferrin at mRNA and protein levels occurred after the treatment with a low dose of methapyrilene that exhibited minimal cytotoxicity. These results demonstrate the significance of the dysregulation of hepatic iron metabolism in the pathogenesis and mechanism of chemical-induced liver toxicity and suggest that these changes may be sensitive and useful indicators of potentially hepatotoxic chemicals.
肝脏作为一个主要的解毒器官和全身铁稳态的主要调节者，很容易受到外源性物质的损害。在本研究中，我们在一项重复剂量的体内毒性研究以及体外培养的人HepaRG细胞中，研究了肝毒性和肝癌致癌物盐酸美吡拉敏对大鼠肝脏铁代谢的影响。通过灌胃以40和80mg/kg体重（bw）/天的剂量给雄性Fischer 344（F344）大鼠施用美吡拉敏6周，导致经典肝毒性相关标记基因和铁稳态相关基因的表达发生变化，尤其是转铁蛋白（Tf）基因出现显著的剂量依赖性下调以及铁蛋白轻链（Ftl）基因上调。在经美吡拉敏处理的分化HepaRG细胞中也出现了TF水平降低和FTL水平升高的情况，这表明在肝脏损伤时细胞铁稳态紊乱方面存在种间和体外-体内相似性。相比之下，在经美吡拉敏处理的大鼠肝脏和HepaRG细胞中，肝毒性标记基因的表达几乎没有重叠。重要的是，在用低剂量美吡拉敏处理后出现了mRNA和蛋白质水平的转铁蛋白降低，而该低剂量美吡拉敏的细胞毒性极小。这些结果证明了肝脏铁代谢失调在化学诱导肝毒性的发病机制和机制中的重要性，并表明这些变化可能是潜在肝毒性化学物质的敏感且有用的指标。
