Morimoto K, Tsuji K, Iio T, Miyata N, Uchida A, Osawa R, Kitsutaka H, Takahashi A
Division of Xenobiotic Metabolism and Disposition, National Institute of Hygienic Sciences, Tokyo, Japan.
Carcinogenesis. 1991 Apr;12(4):703-8. doi: 10.1093/carcin/12.4.703.
DNA damage in the forestomach epithelium of male F344 rats was tested by alkaline elution assay following oral administration of 3-tert-butyl-4-hydroxyanisole (3-BHA) and its free metabolites. Although 1% 3-BHA and 0.001% tert-butylhydroquinone (BHQ) caused no detectable DNA damage, a tert-butylquinone (BQ) treated group showed a significantly higher elution rate than the corn oil and 3-BHA group. Dose-dependent induction of DNA damage in forestomach epithelium by 3-BHA metabolites was compared. BQ showed DNA damaging activity from 0.0001% (1 microgram/ml). On the other hand, BHQ showed the activity at greater than 100 times higher concentration than that of BQ. Six other quinones related to the BQ have been synthesized and examined in vivo for their activity in single strand breaks in forestomach epithelium DNA. The order of the DNA damage was not always correlated with the order of the first reduction potentials of the quinones. 2-Benzylthio-5-tert-butyl-p-benzoquinone (BQSBn-2), 2-phenyl-1,4-benzoquinone and 2,5-di-tert-butyl-p-benzoquinone had higher DNA damaging activity than BQ. The effects of ethylacrylate (EA) pretreatment on the DNA damage by BQ and BQSBn-2 were compared. The DNA damage by BQ was decreased by increasing the EA concentrations. On the other hand, BQSBn-2 had a DNA damaging activity following the EA pretreatment. In order to examine whether 3-BHA is metabolized in forestomach, 3-BHA and BQ levels in the mucosa of forestomach were measured by HPLC with an electrochemical detector. The concentrations of BQ in mucosa correlated with the 3-BHA dose levels from 0.01% to 0.1% 3-BHA. The concentration of BQ in mucosa was approximately 1/4000 of the concentration of 3-BHA in mucosa at the dose level of 1% 3-BHA. The present results indicate that BQ and its thiol conjugates are the active metabolites from 3-BHA in forestomach and may play an important role in inducing carcinogenicity of 3-BHA in F344 rats.
