Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes

Naoya Matsunaga, Yumiko Kohno, Keisuke Kakimoto, Akane Hayashi, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The Clock gene is a core clock factor that plays an essential role in generating circadian rhythms. In the present study, it was investigated whether the Clock gene affects the response to diethylnitrosamine (DEN)-induced cytotoxicity using mouse primary hepatocytes. DEN-induced cytotoxicity, after 24. h exposure, was caused by apoptosis in hepatocytes isolated from wild-type mouse. On the other hand, Clock mutant mouse (Clk/. Clk) hepatocytes showed resistance to apoptosis. Because apoptosis is an important pathway for suppressing carcinogenesis after genomic DNA damage, the mechanisms that underlie resistance to DEN-induced apoptosis were examined in Clk/. Clk mouse hepatocytes. The mRNA levels of metabolic enzymes bioactivating DEN and apoptosis-inducing factors before DEN exposure were lower in Clk/. Clk cells than in wild-type cells. The accumulation of p53 and Ser15 phosphorylated p53 after 8. h DEN exposure was seen in wild-type cells but not in Clk/. Clk cells. Caspase-3/7 activity was elevated during 24. h DEN exposure in wild-type cells but not in Clk/. Clk cells. In addition, resistance to DEN-induced apoptosis in Clk/. Clk cells affected the cell viability. These studies suggested that the lower expression levels of metabolic enzymes bioactivating DEN and apoptosis inducing factors affected the resistance to DEN-induced apoptosis in Clk/. Clk cells, and the Clock gene plays an important role in cytotoxicity induced by DEN.

Original languageEnglish
Pages (from-to)144-151
Number of pages8
JournalToxicology
Volume280
Issue number3
DOIs
Publication statusPublished - Feb 27 2011

All Science Journal Classification (ASJC) codes

  • Toxicology

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