The modifying effects of citrus
auraptene given during the initiation and post-initiation phases of oral
carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats. At 6 weeks of age, animals were divided into experimental and control groups, and fed the diets containing 100 ppm or 500 ppm
auraptene. At 7 weeks of age, all animals except those treated with
auraptene alone and control groups were given 4-NQO (20 ppm) in the
drinking water for 8 weeks to induce tongue
carcinoma. Starting 7 days before the 4-NQO exposure, groups of animals were fed the diets containing
auraptene (100 and 500 ppm) for 10 weeks and then switched to the basal diet. Starting 1 week after the cessation of 4-NQO exposure, the groups given 4-NQO and a basal diet were switched to the diets mixed with
auraptene (100 and 500 ppm), and maintained on these diets for 22 weeks. The other groups consisted of rats fed
auraptene alone (500 ppm) or untreated rats. All rats were necropsied at the termination of the study (week 32). The incidences of tongue lesions (
neoplasms and preneoplasms),
polyamine levels in the tongue tissue and cell proliferation activity estimated by
5-bromodeoxyuridine (
BrdU)-labelling index were compared among the groups. In addition, the activities of gluthathione S-
transferase (GST) and
quinone reductase (QR) in liver and tongue of rats gavaged various doses of
auraptene (0, 200, 400 and 800 mg/kg body wt) for 5 days were assayed. Feeding of
auraptene at both doses during the initiation phase caused a significant reduction in the frequency of tongue
carcinoma (100 ppm
auraptene, 91% reduction, P < 0.001; 500 ppm
auraptene, 63% reduction, P < 0.05). When fed
auraptene after 4-NQO exposure, the frequency of tongue
carcinoma was also decreased (100 ppm
auraptene, 100% reduction, P < 0.001; 500 ppm
auraptene, 74% reduction, P < 0.01). The incidences of tongue severe dysplasia in these groups were significantly smaller than those in
carcinogen controls (P < 0.05). There were no pathological alterations in rats treated with 500 ppm
auraptene alone or those in an untreated control group. Dietary administration of
auraptene significantly decreased
BrdU-labelling index and
polyamine concentrations in the oral mucosa (P < 0.05). In addition,
auraptene administration significantly increased the activities of GST and QR in the liver and tongue. Although dose-dependent effect was not found, citrus
auraptene is effective in inhibiting the development of
oral neoplasms induced by 4-NQO. Thus, suppression by the initiation-feeding of
auraptene might relate to elevation in the phase II
enzymes GST and QR of the liver and tongue, and inhibition occurring during the post-initiation might be related to suppression of increased cell proliferation caused by 4-NQO in the oral mucosa.