title: Possible involvement of sulfotransferase 1A1 in estragole-induced DNA modification and carcinogenesis in the livers of female mice.
abstract: Estragole (ES), a natural organic compound, is frequently used as a flavoring in food even though it is a hepatocarcinogen in mice. Although formation of ES-specific DNA adducts following conversion from ES to the nucleophilic metabolite by sulfotransferase 1A1 (SULT1A1) has been reported, the modes of action underlying ES-induced hepatocarcinogenesis remain uncertain because conventional genotoxicity tests for ES yield negative results. In the present study, taking notice of the fact that there is a sex difference in SULT1A1 activity in the mouse liver, we assessed the frequency of micronuclei in polychromatic erythrocytes and the mutant frequency (MF) of reporter genes in female gpt delta mice treated with ES at doses of 0 (corn oil), 37.5, 75, 150 or 300mg/kg body weight (bw) by gavage for 13 weeks. Results were compared with those obtained in males. Since one female was found dead at week one, the highest dose was reduced to 250mg/kg bw in females from week two. As reported previously in C57BL/6 mice, the mRNA levels of Sult1a1 in female gpt delta mice were significantly higher than those in the males. The levels of ES-specific DNA adducts in the females were higher than those in the males at all doses except the highest dose. In addition, MFs of the gpt gene were significantly increased from doses of 75mg/kg bw of females, but the increment was observed only at the highest dose in males. There were no changes in the micronucleus test among the groups. Thus, the overall data suggest that specific DNA modifications by the SULT1A1-mediated carbocation formation and the resultant genotoxicity are key events in the early stage of ES-induced hepatocarcinogenesis of mice.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Setagayaku, Tokyo, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
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: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
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 / Q000633:toxicity*; D015239:Arylsulfotransferase / Q000378:metabolism*; D018736:DNA Adducts; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005421:Flavoring Agents / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*
chemical_list: D000081248:Allylbenzene Derivatives; D000840:Anisoles; D018736:DNA Adducts; D005421:Flavoring Agents; D009153:Mutagens; C007633:estragole; D015239:Arylsulfotransferase; C513291:Sult1a1 protein, mouse