Effects of Oral Administration of Non-genotoxic Hepato-hypertrophic Compounds on Metabolic Potency of Rat Liver
- 1 January 2014
- journal article
- Published by Japanese Environmental Mutagen Society in Genes and Environment
- Vol. 36 (1), 1-9
- https://doi.org/10.3123/jemsge.2013.011
Abstract
It remains uncertain why non-genotoxic compounds that result in liver hypertrophy cause liver tumors. In an effort to resolve this issue, we examined whether liver post-mitochondrial fraction (S9) prepared from rats treated with non-genotoxic compounds affected the genotoxicity of pro-mutagens. Known hepatotoxic compounds, such as piperonyl butoxide (PBO), decabromodiphenyl ether (DBDE), beta-naphthoflavone (BNF), indole-3-carbinol (I3C) and acetaminophen (AA), were orally administered to male and female F344 rats at doses sufficient to cause liver hypertrophy. Rats received diets containing each test compound for 3 days, 4 weeks or 13 weeks, and were then kept for 4 weeks without the test chemical. S9 prepared from the livers of each group was used for the Ames test with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (BaP) and N-nitrosodimethylamine (NDMA). In both sexes, liver hypertrophy was observed following administration of all test compounds, and was then reversed to the control state when administration ceased. The mutagenicity of MeIQx, BaP and NDMA increased with the use of S9 derived from rats treated with non-genotoxic compounds other than AA. DBDE administration had a marked effect on the mutagenicity of BaP (over a 30-fold increase in females) and NDMA (about a 20-fold increase in males). To estimate the involvement of metabolic enzymes in the alteration of mutagenicity, we measured the activity of ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-demethylase (MROD) (phase I enzymes), and UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) (phase II enzymes) in each S9 sample. The activity of phase I enzymes increased, even at the 3rd day following administration, and then decreased gradually, except in the case of AA, while the activity of phase II enzymes increased slightly. These results suggest that non-genotoxic hepato-hypertrophic compounds may be partly involved in carcinogenesis by modulating the metabolism of pre-carcinogens incorporated from the environment, in a manner that is dependent on sex and pre-incorporated chemicals.Keywords
This publication has 32 references indexed in Scilit:
- Toxicity of penta- and decabromodiphenyl ethers after repeated administration to rats: a comparative studyArchives of Toxicology, 2009
- Molecular pathological analysis for determining the possible mechanism of piperonyl butoxide-induced hepatocarcinogenesis in miceToxicology, 2006
- CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical ImplicationsPharmaceutical Research, 2006
- Supplement to the Carcinogenic Potency Database (CPDB): Results of Animal Bioassays Published in the General Literature through 1997 and by the National Toxicology Program in 1997–1998Toxicological Sciences, 2005
- Live Tumor-Promoting Effect of β-Naphthoflavone, a Strong CYP 1A1/2 Inducer, and the Relationship between CYP 1A1/2 Induction and Cx32 Decrease in Its Hepatocarcinogenesis in the RatToxicologic Pathology, 2000
- Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosisBiochemical Pharmacology, 1999
- Chronic toxicity studies of piperonyl butoxide in CD-1 mice: Induction of hepatocellular carcinomaToxicology, 1997
- Marketed Human Pharmaceuticals Reported to be Tumorigenic in RodentsJournal of the American College of Toxicology, 1995
- Chronic Toxicity Studies of Piperonyl Butoxide in F344 Rats: Induction of Hepatocellular CarcinomaFundamental and Applied Toxicology, 1994
- Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liverMutation research. Reviews in mutation research, 1991