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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2009-2-19
pubmed:abstractText
Two-year treatment with high doses of Metofluthrin produced hepatocellular tumors in both sexes of Wistar rats. To understand the mode of action (MOA) by which the tumors are produced, a series of studies examined the effects of Metofluthrin on hepatic microsomal cytochrome P450 (CYP) content, hepatocellular proliferation, hepatic gap junctional intercellular communication (GJIC), oxidative stress and apoptosis was conducted after one or two weeks of treatment. The global gene expression profile indicated that most genes with upregulated expression with Metofluthrin were metabolic enzymes that were also upregulated with phenobarbital. Metofluthrin induced CYP2B and increased liver weights associated with centrilobular hepatocyte hypertrophy (increased smooth endoplasmic reticulum [SER]), and induction of increased hepatocellular DNA replication. CYP2B1 mRNA induction by Metofluthrin was not observed in CAR knockdown rat hepatocytes using the RNA interference technique, demonstrating that Metofluthrin induces CYP2B1 through CAR activation. Metofluthrin also suppressed hepatic GJIC and induced oxidative stress and increased antioxidant enzymes, but showed no alteration in apoptosis. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. All of these effects were reversible upon cessation of treatment. Metofluthrin did not cause cytotoxicity or peroxisome proliferation. Thus, it is highly likely that the MOA for Metofluthrin-induced liver tumors in rats is through CYP induction and increased hepatocyte proliferation, similar to that seen for phenobarbital. Based on analysis with the International Life Sciences Institute/Risk Science Institute MOA framework, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans, at least at expected levels of exposure.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1096-0929
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
108
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
69-80
pubmed:dateRevised
2010-9-17
pubmed:meshHeading
pubmed-meshheading:19176366-Animals, pubmed-meshheading:19176366-Apoptosis, pubmed-meshheading:19176366-Aryl Hydrocarbon Hydroxylases, pubmed-meshheading:19176366-Cell Proliferation, pubmed-meshheading:19176366-Cyclopropanes, pubmed-meshheading:19176366-Cytochrome P-450 CYP2B1, pubmed-meshheading:19176366-Disease Models, Animal, pubmed-meshheading:19176366-Female, pubmed-meshheading:19176366-Fluorobenzenes, pubmed-meshheading:19176366-Gene Expression Regulation, Neoplastic, pubmed-meshheading:19176366-Liver, pubmed-meshheading:19176366-Liver Neoplasms, Experimental, pubmed-meshheading:19176366-Male, pubmed-meshheading:19176366-Microsomes, Liver, pubmed-meshheading:19176366-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:19176366-Oxidative Stress, pubmed-meshheading:19176366-Phenobarbital, pubmed-meshheading:19176366-Pyrethrins, pubmed-meshheading:19176366-RNA Interference, pubmed-meshheading:19176366-Rats, pubmed-meshheading:19176366-Rats, Wistar, pubmed-meshheading:19176366-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:19176366-Statistics, Nonparametric
pubmed:year
2009
pubmed:articleTitle
Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation.
pubmed:affiliation
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-8558, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't