Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation.
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.
Deguchi
Yoshihito
Y
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-8558, Japan.
Yamada
Tomoya
T
Hirose
Yukihiro
Y
Nagahori
Hirohisa
H
Kushida
Masahiko
M
Sumida
Kayo
K
Sukata
Tokuo
T
Tomigahara
Yoshitaka
Y
Nishioka
Kazuhiko
K
Uwagawa
Satoshi
S
Kawamura
Satoshi
S
Okuno
Yasuyoshi
Y
D000818:Animals; D017209:Apoptosis; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes / Q000633:toxicity*; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005464:Fluorobenzenes / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010634:Phenobarbital / Q000633:toxicity; D011722:Pyrethrins / Q000633:toxicity; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric
D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D005464:Fluorobenzenes; D011722:Pyrethrins; D018160:Receptors, Cytoplasmic and Nuclear; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C492600:(2,3,5,6-tetrafluoro-4-methoxymethylphenyl)methyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate; D010634:Phenobarbital