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Archives of Toxicology

, Volume 72, Issue 11, pp 744–750 | Cite as

Mechanistic study on liver tumor promoting effects of piperonyl butoxide in rats

  • Hideaki Okamiya
  • Kunitoshi Mitsumori
  • Hiroshi Onodera
  • Seiichi Ito
  • Takayoshi Imazawa
  • Kazuo Yasuhara
  • Michihito Takahashi
ORGAN TOXICITY AND MECHANISMS

Abstract

Piperonyl butoxide, alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltoluene, is a widely used pesticide-synergist. Recently, results were reported indicating that piperonyl butoxide is a hepatocarcinogen in rat. Since the underlying mechanism was not elucidated, we examined the effects on rat liver cells in detail. For this purpose male F344 rats were administered piperonyl butoxide mixed in the diet at concentrations of 0 (negative control), 0.05, 0.2 or 2% for 2 days, 1, 2, and 4 weeks. As a positive control, phenobarbital was administered to rats for up to 4 weeks as a 0.1% solution in the drinking water. Increased liver weight, centrilobular hepatocellular hypertrophy due to increased smooth endoplasmic reticulum, decreased numbers and areas of connexin 32-positive spots per hepatocyte, and increased cell proliferation were observed in rats treated with 0.2 and 2% piperonyl butoxide. Similar results were obtained for 0.1% phenobarbital treated rats. Hepatocellular necrosis suggestive of hepatotoxicity was also observed in the 2% piperonyl butoxide group. These results indicate that the promoting mechanism of piperonyl butoxide in hepatocarcinogenesis is similar to that of phenobarbital, involving an ability to induce CYP isoenzymes and inhibit gap junctional intercellular communication. In addition, increased cell proliferation following hepatocellular necrosis may also play a role at high doses.

Key words Piperonyl butoxide Phenobarbital Hepatocarcinogenesis promoting mechanism Gap junctional intercellular communication Cell proliferating activity 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Hideaki Okamiya
    • 1
  • Kunitoshi Mitsumori
    • 2
  • Hiroshi Onodera
    • 2
  • Seiichi Ito
    • 3
  • Takayoshi Imazawa
    • 2
  • Kazuo Yasuhara
    • 2
  • Michihito Takahashi
    • 2
  1. 1.Medicinal Safety Laboratories, Yamanouchi Pharmaceutical Co. Ltd., Azusawa 1-1-8, Itabashi-ku, Tokyo 174, JapanJP
  2. 2.Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158, JapanJP
  3. 3.Pathologic Division, Nippon Experimental Medical Research Institute Co. Ltd., Nakasatomi 416, Haruna-machi, Gunma-gun, Gunma 370-33, JapanJP

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