Role of CYP2E1 in diethylnitrosamine-induced hepatocarcinogenesis in vivo

• Published in: Cancer research (Chicago, Ill.) Ill.), 2007-12, Vol.67 (23), p.11141-11146
• Main Authors: Kang, Jin Seok, Wanibuchi, Hideki, Morimura, Keiichirou, Gonzalez, Frank J, Fukushima, Shoji
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; bcl-2-Associated X Protein - metabolism; Blotting, Western; Carcinogens - toxicity; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Caspase 3 - metabolism; Cytochrome P-450 CYP2E1 - genetics; Cytochrome P-450 CYP2E1 - physiology; Diethylnitrosamine - toxicity; Genotype; Liver Neoplasms, Experimental - enzymology; Liver Neoplasms, Experimental - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-07-1369

CYP2E1 metabolizes many low-molecular weight toxins and carcinogens. Some in vitro experiments suggest that CYP2E1 may be involved in the metabolic activation of diethylnitrosamine. However, there has been no direct evidence demonstrating a role for CYP2E1 in diethylnitrosamine-mediated carcinogenesis in vivo. To clarify this, we carried out a diethylnitrosamine-induced hepatocarcinogenesis experiment using Cyp2e1-null mice. Male 14-day-old wild-type and Cyp2e1-null mice were treated with diethylnitrosamine (10 mg/kg of body weight) and killed at weeks 24 and 36 after diethylnitrosamine treatment for investigation of tumors and at 6, 24, and 48 h for examination of apoptosis and gene expression. Liver weights of Cyp2e1-null mice were significantly different at weeks 24 and 36 compared with wild-type mice (P < 0.01). Liver tumor incidences of Cyp2e1-null mice were significantly decreased at weeks 24 and 36 compared with wild-type mice (P < 0.01). Cyp2e1-null mice showed significant decrease in the multiplicities of hepatocellular adenoma at weeks 24 and 36 (P < 0.05 and P < 0.01, respectively), and of hepatocellular carcinoma at week 36 (P < 0.01) compared with wild-type mice. Apoptotic index and caspase-3 and/or Bax mRNA expression of Cyp2e1-null mice were significantly different at 6, 24, and 48 h after diethylnitrosamine treatment compared with wild-type mice (P < 0.05). We conclude that Cyp2e1-null mice show lower tumor incidence and multiplicity compared with wild-type mice in diethylnitrosamine-induced hepatocarcinogenesis. It is suggested that CYP2E1 completely participates in diethylnitrosamine-induced hepatocarcinogenesis, and high frequency of tumors in wild-type mice could be associated with the increased apoptosis.