In vivo genotoxicity of methyleugenol in gpt delta transgenic rats following medium-term exposure.
Methyleugenol (MEG), which is commonly used as a fragrance and flavoring agent, has been shown to induce hepatocellular tumors in rodents. However, the role of genotoxicity as a possible mechanism of action is not fully understood even though the DNA-reactive metabolite of MEG has been identified. In this study, a gpt delta transgenic rat model was used to clarify whether genotoxic mechanisms are involved in MEG-induced hepatocarcinogenesis following medium-term exposure. F344 gpt delta rats were subjected to repeated oral administration of MEG at dosages of 0, 10, 30, or 100mg/kg (a carcinogenic dose) for 13 weeks. The relative weight of the liver of the male and female rats that were administered 100mg/kg MEG and the absolute weight of the liver of the male rats that were administered 100mg/kg MEG were significantly increased. In addition, the number and area of glutathione S-transferase placental form (GST-P) positive foci and proliferating cell nuclear antigen (PCNA) positive cell ratios in the hepatocytes were significantly increased in the male and female rats that were administered 100mg/kg MEG compared with the control animals. In the in vivo mutation assays, a significant increase in the gpt and Spi(-) mutant frequencies was observed in both sexes at the carcinogenic dose. These results suggest the possible participation of genotoxic mechanisms in MEG-induced hepatocarcinogenesis.
Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
Meilan
M
Jin
Aki
A
Kijima
Daisuke
D
Hibi
Yuji
Y
Ishii
Shinji
S
Takasu
Kohei
K
Matsushita
Ken
K
Kuroda
Takehiko
T
Nohmi
Akiyoshi
A
Nishikawa
Takasi
T
Umemura
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005054:Eugenol / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
D009153:Mutagens; C005223:methyleugenol; D005054:Eugenol; D017855:Transferases (Other Substituted Phosphate Groups); C106504:UDP-GlcNAc-undecaprenyl phosphate N-acetylglucosaminyl 1-phosphate transferase