title: Involvement of Mouse Constitutive Androstane Receptor in Acifluorfen-Induced Liver Injury and Subsequent Tumor Development.
abstract: Acifluorfen (ACI), a protoporphyrinogen oxidase (PROTOX) inhibitor herbicide, promotes the accumulation of protoporphyrin IX (PPIX), and induces tumors in the rodent liver. Porphyria is a risk factor for liver tumors in humans; however, the specific mechanisms through which ACI induces hepatocarcinogenesis in rodents are unclear. Here, we investigated the mode of action of ACI-induced hepatocarcinogenesis, focusing on constitutive androstane receptor (CAR, NR1I3), which is essential for the development of rodent liver tumors in response to certain cytochrome P450 (CYP) 2B inducers. Dietary treatment with 2500 ppm ACI for up to 13 weeks increased Cyp2b10 expression in the livers of wild-type (WT) mice, but not in CAR-knockout (CARKO) mice. Microscopically, ACI treatment-induced cytotoxic changes, including hepatocellular necrosis and inflammation, and caused regenerative changes accompanied by prolonged increases in the numbers of proliferating cell nuclear antigen-positive hepatocytes in WT mice. In contrast, these cytotoxic and regenerative changes in hepatocytes were significantly attenuated, but still observed, in CARKO mice. ACI treatment also increased liver PPIX levels similarly in both genotypes; however, no morphological evidence of porphyrin deposition was found in hepatocytes from either genotype. Treatment with 2500 ppm ACI for 26 weeks after initiation with diethylnitrosamine increased the incidence and multiplicities of altered foci and adenomas in hepatocytes from WT mice; these effects were significantly reduced in CARKO mice. These results indicated that prolonged cytotoxicity in the liver was a key factor for ACI-induced hepatocarcinogenesis, and that CAR played an important role in ACI-induced liver injury and tumor development in mice.
authors.affiliation: *Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan Safety Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kuwata
authors.affiliation: *Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan Food Safety Commission, Cabinet Office, Akasaka Park Bld 22F, 5-2-20 Akasaka, Minato-ku, Tokyo 107-6122, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.affiliation: *Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ichimura
authors.affiliation: *Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Toxicology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
authors.affiliation: Food Safety Commission, Cabinet Office, Akasaka Park Bld 22F, 5-2-20 Akasaka, Minato-ku, Tokyo 107-6122, Japan midori.yoshida@cao.go.jp.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000236:Adenoma / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000090702:Constitutive Androstane Receptor; D000072467:Cytochrome P450 Family 2 / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D005838:Genotype; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009336:Necrosis; D009579:Nitrobenzoates / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011524:Protoporphyrins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism; D013997:Time Factors
chemical_list: D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D009579:Nitrobenzoates; C000716328:Nr1i3 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D011524:Protoporphyrins; D018160:Receptors, Cytoplasmic and Nuclear; D004052:Diethylnitrosamine; C028025:protoporphyrin IX; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2; C018425:acifluorfen
keywords: acifluorfen; constitutive androstane receptor; cytotoxicity; liver tumorigenesis; porphyrin.