Comparison of the effects of the synthetic pyrethroid Metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes.
High doses of Metofluthrin (MTF) have been shown to produce liver tumours in rats by a mode of action (MOA) involving activation of the constitutive androstane receptor leading to liver hypertrophy, induction of cytochrome P450 (CYP) forms and increased cell proliferation. The aim of this study was to compare the effects of MTF with those of the known rodent liver tumour promoter phenobarbital (PB) on the induction CYP2B forms and replicative DNA synthesis in cultured rat and human hepatocytes. Treatment with 50 microM MTF and 50 microM PB for 72 h increased CYP2B1 mRNA levels in male Wistar rat hepatocytes and CYP2B6 mRNA levels in human hepatocytes. Replicative DNA synthesis was determined by incorporation of 5-bromo-2'-deoxyuridine over the last 24 h of a 48 h treatment period. Treatment with 10-1000 microM MTF and 100-500 microM PB resulted in significant increases in replicative DNA synthesis in rat hepatocytes. While replicative DNA synthesis was increased in human hepatocytes treated with 5-50 ng/ml epidermal growth factor or 5-100 ng/ml hepatocyte growth factor, treatment with MTF and PB had no effect. These results demonstrate that while both MTF and PB induce CYP2B forms in both species, MTF and PB only induced replicative DNA synthesis in rat and not in human hepatocytes. These results provide further evidence that the MOA for MTF-induced rat liver tumour formation is similar to that of PB and some other non-genotoxic CYP2B form inducers and that the key event of increased cell proliferation would not occur in human liver.
Hirose
Yukihiro
Y
Environmental Health Science Laboratory, Sumitomo Chemical Company Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-8558, Japan.
Nagahori
Hirohisa
H
Yamada
Tomoya
T
Deguchi
Yoshihito
Y
Tomigahara
Yoshitaka
Y
Nishioka
Kazuhiko
K
Uwagawa
Satoshi
S
Kawamura
Satoshi
S
Isobe
Naohiko
N
Lake
Brian G
BG
Okuno
Yasuyoshi
Y
D000328:Adult; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000633:toxicity*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis*; D065702:Cytochrome P-450 CYP2B6; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D005464:Fluorobenzenes / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D010634:Phenobarbital / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D003521:Cyclopropanes; D005464:Fluorobenzenes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D019362:Cytochrome P-450 CYP2B1; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C492600:(2,3,5,6-tetrafluoro-4-methoxymethylphenyl)methyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate; D010634:Phenobarbital