title: Possible involvement of genotoxic mechanisms in estragole-induced hepatocarcinogenesis in rats.
abstract: Estragole (ES) is a natural organic compound used frequently as a flavoring food additive. Although it has been reported to be tumorigenic and induce DNA adducts in the mouse liver, there have been no reports regarding ES hepatocarcinogenicity in rats. In the current study, we therefore examined potent carcinogenicity, DNA adduct formation and in vivo genotoxicity of ES in the livers of wild and reporter gene-carrying F344 rats. Males were administered 600 mg/kg bw ES by gavage and sequentially sacrificed at weeks 4, 8 and 16 for GST-P and PCNA immunohistochemistry and measurement of ES-specific DNA adducts by LC-MS/MS in the livers. GST-P-positive foci increased with time in ES-treated rats from week 4, PCNA-labeling indices being similarly elevated at both weeks 4 and 8. ES-specific DNA adducts such as ES-3'-N(2)-dG, 3'-8-dG and 3'-N(6)-dA were consistently detected, particularly at week 4. In a second study, male F344 gpt delta rats were administered 0, 22, 66, 200 or 600 mg/kg bw ES for 4 weeks. Gpt mutant frequency in the liver was increased in a dose-dependent manner, with significance at 200 and 600 mg/kg bw in good correlation with PCNA-labeling indices. Mutation spectra analysis showed A:T to G:C transitions to be predominantly increased in line with the formation of ES-3'-N(6)-dA or 3'-8-dG. These results indicate that ES could be a possible genotoxic hepatocarcinogen in the rat, at least when given at high doses.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hibi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Inoue
authors.forename: Meilan
authors.initials: M
authors.lastname: Jin
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Tokuma
authors.initials: T
authors.lastname: Yanai
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000633:toxicity*; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005421:Flavoring Agents / Q000008:administration & dosage / Q000633:toxicity*; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D000081248:Allylbenzene Derivatives; D000840:Anisoles; D018736:DNA Adducts; D005421:Flavoring Agents; D009153:Mutagens; D018809:Proliferating Cell Nuclear Antigen; C007633:estragole; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat