Clinical cisplatin use is often limited by its drug-induced liver injury (DILI). Particularly, individual differences in susceptibility to DILI can cause life-threatening medical conditions. This study aimed to uncover the inherent genetic factors determining individual variations in hepatotoxicity susceptibility. Rats were subjected to liver biopsy and a 3-week postoperative recovery period before cisplatin administration. At 2 days post-treatment with cisplatin, the rats exhibited histopathological and serum biochemical alterations in the liver, and changes in hydrogen peroxide and cytochrome P450-2E1 levels. Based on these results of liver-related biochemical markers, 32 rats were grouped into the susceptible (top five) and resistant (bottom five) groups. Using RNA-sequencing, we compared gene expressions in the liver pre-biopsied from these two groups before cisplatin treatment and found 161 differently expressed genes between the Susceptible and Resistant groups. Among them, the clock-controlled Ccrn4l responsible for 'rhythmic process' was identified as a common gene downregulated inherently prior to drug exposure in both cisplatin- and acetaminophen-sensitive animals. Additionally, low Ccrn4l levels before cisplatin treatment in the Susceptible group were maintained even after treatment, with decreased antioxidants, increased nitration, and apoptosis. The relationship of Ccrn4l with catalase and mitochondrial RNAs in the liver was confirmed by correlation of their hepatic levels among individuals and similar patterns of circadian variation in their mRNA expression. Remarkably, Ccrn4l knockdown promoted cisplatin-induced mitochondrial dysfunction in WB-F344 cells with antioxidant catalase and apoptosis-related Bax changes. Inherent individual hepatic Ccrn4l level might be a novel factor affecting cisplatin-induced hepatotoxicity susceptibility, possibly through regulation of mitochondrial and antioxidant functions.

中文翻译：

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Ccrn4l作为预测顺铂诱导的肝毒性敏感性的剂量前标志物。

顺铂的临床使用通常受到药物诱导的肝损伤（DILI）的限制。特别是，对DILI的易感性的个体差异会导致危及生命的医疗状况。这项研究旨在揭示决定肝毒性敏感性个体差异的内在遗传因素。顺铂给药前，对大鼠进行肝活检和术后3周恢复期。用顺铂治疗后第2天，大鼠肝脏表现出组织病理学和血清生化改变，并且过氧化氢和细胞色素P450-2E1水平发生变化。根据肝脏相关生化标记物的这些结果，将32只大鼠分为敏感组（前五名）和耐药组（下五名）。使用RNA测序 我们比较了这两组在顺铂治疗之前预先活检的肝脏中的基因表达，发现在敏感和耐药组之间有161个差异表达的基因。其中，负责“节律性过程”的时钟控制的Ccrn41被确定为在对顺铂和对乙酰氨基酚敏感的动物中暴露于药物之前固有地被下调的常见基因。另外，即使在治疗后，易感组中顺铂治疗前的Ccrn41水平仍保持低水平，抗氧化剂减少，硝化作用增加和细胞凋亡。肝中Ccrn41与过氧化氢酶和线粒体RNA的关系通过个体之间的肝水平相关性和其mRNA表达的昼夜节律变化的相似模式得到证实。值得注意的是 Ccrn4l敲低促进了顺铂诱导的WB-F344细胞中的线粒体功能障碍，具有抗氧化过氧化氢酶和凋亡相关的Bax变化。固有的个体肝脏Ccrn4l水平可能是影响顺铂诱导的肝毒性敏感性的新因素，可能是通过调节线粒体和抗氧化功能来实现的。