Abstract
Isoeugenol (IEG) is a natural alkenylbenzene compound which is used as a flavoring additive in foods. However, it has been shown to
be a hepatocarcinogen in male B6C3F1 mice. Although there are negative results in several genotoxicity tests, the genotoxicity of IEG
in the livers of male mice has not been investigated. To determine whether a genotoxic mechanism is involved in hepatocarcinogenesis,
we carried out histopathological analyses, comprehensive DNA adduct analyses, in vivo mutation assays and global gene expression
analyses in the livers of male and female B6C3F1 gpt delta mice treated with IEG by gavage at doses of 0, 150, 300 or 600 mg/kg bw/
day for 13 weeks. IEG induced slight hepatocyte hypertrophy along with liver weight gain in male mice treated with 300 mg/kg bw/day
IEG and more, but not in similarly treated female mice. Comprehensive DNA adduct analyses by LC-MS/MS showed no specific DNA
adduct formation in the liver, and there were no changes in gpt or Spi-
mutant frequencies in the livers. A pathway analysis of mRNA
expression data as determined with a cDNA microarray suggested activation of pathways associated with peroxisome proliferator activated receptor (PPAR) α and γ in the livers of male mice. Overall, our data show a lack of genotoxicity in the mechanisms leading to
the hepatocarcinogenesis of IEG in mice, and they suggest the involvement of PPARα and γ pathway activation in this process.
