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Title: A mode of action for induction of liver tumors by Pyrethrins in the rat

High doses of Pyrethrins produce liver tumors in female rats. To elucidate the mode of action for tumor formation, the hepatic effects of Pyrethrins have been investigated. Male Sprague-Dawley CD rats were fed diets containing 0 (control) and 8000 ppm Pyrethrins and female rats' diets containing 0, 100, 3000 and 8000 ppm Pyrethrins for periods of 7, 14 and 42 days and 42 days followed by 42 days of reversal. As a positive control, rats were also fed diets containing 1200-1558 ppm sodium Phenobarbital (NaPB) for 7 and 14 days. The treatment of male rats with 8000 ppm Pyrethrins, female rats with 3000 and 8000 ppm Pyrethrins and both sexes with NaPB resulted in increased liver weights, which were associated with hepatocyte hypertrophy. Hepatocyte replicative DNA synthesis was also increased by treatment with Pyrethrins and NaPB. The treatment of male and female rats with Pyrethrins and NaPB produced significant increases in hepatic microsomal cytochrome P450 (CYP) content and a marked induction of CYP2B-dependent 7-pentoxyresorufin O-depentylase and testosterone 16{beta}-hydroxylase activities. Significant increases were also observed in CYP3A-dependent testosterone 6{beta}-hydroxylase activity. The hepatic effects of Pyrethrins were dose-dependent in female rats with 100 ppm being a no effect level and on cessationmore » of treatment were reversible in both sexes. This study demonstrates that Pyrethrins are mitogenic CYP2B form inducers in rat liver. The mode of action for Pyrethrins-induced rat liver tumor formation appears to be similar to that of NaPB and some other non-genotoxic CYP2B inducers of hepatic xenobiotic metabolism.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [1]
  1. BIBRA International Ltd, Woodmansterne Road, Carshalton, Surrey, SM5 4DS (United Kingdom) and Centre for Toxicology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH (United Kingdom)
  2. BIBRA International Ltd, Woodmansterne Road, Carshalton, Surrey, SM5 4DS, England and Centre for Toxicology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH (United Kingdom)
  3. Inveresk Research, Tranent, EH33 2NE, Scotland (United Kingdom)
  4. ConTox Ltd, Fort Washington, PA 19034-0368 (United States)
  5. Ohio State University, Columbus, OH 43082 (United States)
  6. Science Strategies LLC, Charlottesville, VA 22902 (United States). E-mail: tom@sciencestrategies.com
Publication Date:
OSTI Identifier:
20976852
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 218; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2006.11.004; PII: S0041-008X(06)00416-9; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOSYNTHESIS; CARCINOGENS; DIET; DNA; ENZYME INDUCTION; HYDROXYLASES; HYPERTROPHY; LIVER; METABOLISM; NEOPLASMS; PHENOBARBITAL; RATS; SEX; SODIUM; TESTOSTERONE