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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)128-139
Number of pages12
JournalFree Radical Biology and Medicine
Volume148
DOIs
StatePublished - 20 Feb 2020

Fingerprint

Cisplatin
Liver
Chemical and Drug Induced Liver Injury
Rats
Antioxidants
Catalase
Genes
Pharmaceutical Preparations
Apoptosis
RNA Sequence Analysis
Nitration
Cytochrome P-450 CYP2E1
Biopsy
Therapeutics
Acetaminophen
Postoperative Period
Gene expression
Individuality
Hydrogen Peroxide
Clocks

Keywords

  • Cisplatin
  • Hepatotoxicity
  • Individual variation
  • Pre-biopsy method
  • Susceptibility

Cite this

Hwang, Da Bin ; Won, Dong Hoon ; Shin, Yoo Sub ; Kim, Shin Young ; Kang, Byeong Cheol ; Lim, Kyung Min ; Che, Jeong Hwan ; Nam, Ki Taek ; Yun, Jun Won. / Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility. In: Free Radical Biology and Medicine. 2020 ; Vol. 148. pp. 128-139.
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Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility. / Hwang, Da Bin; Won, Dong Hoon; Shin, Yoo Sub; Kim, Shin Young; Kang, Byeong Cheol; Lim, Kyung Min; Che, Jeong Hwan; Nam, Ki Taek; Yun, Jun Won.

In: Free Radical Biology and Medicine, Vol. 148, 20.02.2020, p. 128-139.

Research output: Contribution to journalArticle

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T1 - Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility

AU - Hwang, Da Bin

AU - Won, Dong Hoon

AU - Shin, Yoo Sub

AU - Kim, Shin Young

AU - Kang, Byeong Cheol

AU - Lim, Kyung Min

AU - Che, Jeong Hwan

AU - Nam, Ki Taek

AU - Yun, Jun Won

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AB - 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.

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