Archives of Toxicology

, Volume 73, Issue 7, pp 373–380

The relationship between decrease in Cx32 and induction of P450 isozymes in the early phase of clofibrate hepatocarcinogenesis in the rat

  • Toshiyuki Shoda
  • Kunitoshi Mitsumori
  • Hiroshi Onodera
  • Kazuhiro Toyoda
  • Chikako Uneyama
  • Takayoshi Imazawa
  • Masao Hirose
MOLECULAR TOXICOLOGY

DOI: 10.1007/s002040050676

Cite this article as:
Shoda, T., Mitsumori, K., Onodera, H. et al. Arch Toxicol (1999) 73: 373. doi:10.1007/s002040050676

Abstract

To examine the relationship between the decrease in connexin 32 (Cx32) and induction of P450 isozymes in the early phase of clofibrate hepatocarcinogenesis, a total of 20 male F344 rats were initiated with a single intraperitoneal injection of 150 mg/kg of diethylnitrosamine (DEN) or given the saline vehicle alone and starting 2 weeks later given diet containing 0.18, 0.09, and 0% clofibrate for 6 weeks. All animals were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Absolute and relative (ratios to body weight) liver weights were significantly increased in the DEN + clofibrate groups compared with the DEN-alone group. Diffuse hepatocellular hypertrophy with granular cytoplasmic eosinophilia characterized by a marked increase in peroxisomes and smooth endoplasmic reticulum, was observed in the clofibrate treated rats. Induction of cytochrome P450 (CYP) 4A1 and 2B1/2 was noted in the DEN + clofibrate groups, this being most marked in the CYP 2B1 case. Immunohistochemically, positive immunostaining for anti-CYP 4A1 and CYP 2B1 were observed diffusely and centrilobularly, respectively. The numbers and areas of Cx32-positive spots per hepatocyte in the centrilobular areas in the treated rats were significantly decreased in an essentially dose-dependent manner, but no changes were observed in periportal areas. The numbers and areas of foci positive for glutathione S-transferase placental form (GST-P) were decreased in a dose dependent manner in the clofibrate treated groups. These results suggest that the CYP 2B1/2 induction and Cx32 decrease in centrilobular hepatocytes, similarly to those thought to be involved in the hepatic promotion mechanism of phenobarbital, may also play important roles in clofibrate actions in the liver, in addition to its causation of oxidative DNA injury.

Key words Clofibrate Connexin Liver Promotion P450 

Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • Toshiyuki Shoda
    • 1
  • Kunitoshi Mitsumori
    • 1
  • Hiroshi Onodera
    • 1
  • Kazuhiro Toyoda
    • 1
  • Chikako Uneyama
    • 1
  • Takayoshi Imazawa
    • 1
  • Masao Hirose
    • 1
  1. 1.Division of Pathology, National Institute of Health Sciences 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan e-mail: mitsumor@nihs.go.jp Tel.: +81-3-3700-9845, Fax: +81-3-3700-1425JP
  2. 2.Section of Safety, Research Laboratories, Torii Pharmaceutical Co., Ltd., 1-2-1 Ohnodai, Midori-ku, Chiba-shi, Chiba 267-0056, JapanJP

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