title: Different pathways of constitutive androstane receptor-mediated liver hypertrophy and hepatocarcinogenesis in mice treated with piperonyl butoxide or decabromodiphenyl ether.
abstract: The constitutive androstane receptor (CAR) is essential for Cyp2b induction, liver hypertrophy, and hepatocarcinogenesis in response to phenobarbital (PB). Liver hypertrophy with Cyp2b induction is a major mode of action of hepatocarcinogenesis in rodents. However, it remains unclear whether CAR is involved in the response to many other nongenotoxic hepatocarcinogens besides PB. In this study, we investigated CAR involvement in liver hypertrophy and hepatocarcinogenesis of Cyp2b-inducing nongenotoxic hepatocarcinogens, piperonyl butoxide (PBO), and decabromodiphenyl ether (DBDE), using wild-type and CAR knockout (CARKO) male mice. PB was used as the positive control. In the wild-type mice, 4-week treatment with PBO, DBDE, or PB induced hepatocellular hypertrophy with increased Cyp2b10 messenger RNA and Cyp2b protein expression. In CARKO mice, only PBO showed liver hypertrophy with Cyp2b10 and Cyp3a11 induction. After 27-week treatment following diethylnitrosamine initiation, PBO and PB generated many eosinophilic altered foci/adenomas in wild-type mice; however, the lesions were far less frequent in CARKO mice. DBDE increased the multiplicity of basophilic altered foci/adenomas in wild-type and CARKO mice. Our findings indicate that murine CAR plays major roles in hepatocarcinogenesis but not in liver hypertrophy of PBO. DBDE may act via CAR-independent pathways during hepatocarcinogenesis.
authors.affiliation: 1Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Taketa
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Nemoto
authors.forename: Masakuni
authors.initials: M
authors.lastname: Degawa
authors.forename: Toshie
authors.initials: T
authors.lastname: Gamou
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010882:Piperonyl Butoxide / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; D055768:Halogenated Diphenyl Ethers; D018160:Receptors, Cytoplasmic and Nuclear; D001189:Aryl Hydrocarbon Hydroxylases; D010882:Piperonyl Butoxide; C010902:decabromobiphenyl ether
keywords: CAR; Cyp2b; decabromodiphenyl ether.; hepatocarcinogenesis; liver hypertrophy; mice; piperonyl butoxide