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Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility

Authors
 Da-Bin Hwang  ;  Dong-Hoon Won  ;  Yoo-Sub Shin  ;  Shin-Young Kim  ;  Byeong-Cheol Kang  ;  Kyung-Min Lim  ;  Jeong-Hwan Che  ;  Ki Taek Nam  ;  Jun-Won Yun 
Citation
 FREE RADICAL BIOLOGY AND MEDICINE, Vol.148 : 128-139, 2020 
Journal Title
 FREE RADICAL BIOLOGY AND MEDICINE 
ISSN
 0891-5849 
Issue Date
2020
Keywords
Cisplatin ; Hepatotoxicity ; Individual variation ; Pre-biopsy method ; Susceptibility
Abstract
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.
Full Text
https://www.sciencedirect.com/science/article/pii/S0891584919322051
DOI
10.1016/j.freeradbiomed.2020.01.003
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Nam, Ki Taek(남기택)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175236
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