CHEMOPREVENTION OF 4-NITROQUINOLINE 1-OXIDE-INDUCED ORAL CARCINOGENESIS BY CITRUS AURAPTENE IN RATS

The modifying effects of citrus auraptene given during the initiation and post-initiation phases of oral carcinogenesis initiated with 4-nit roquinoline 1-oxide (4-NQO) were investigated in male F344 rats. At 6 weeks of age, animals were divided into experimental and control group s, and fed the diets containing 100 ppm or 500 ppm auraptene. At 7 wee ks of age, all animals except those treated with auraptene alone and c ontrol groups were given 4-NQO (20 ppm) in the drinking water for 8 we eks to induce tongue carcinoma. Starting 7 days before the 4-NQO expos ure, groups of animals were fed the diets containing auraptene (100 an d 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 a nd a basal diet were switched to the diets mixed with auraptene (100 a nd 500 ppm), and maintained on these diets for 22 weeks. The other gro ups consisted of rats fed auraptene alone (500 ppm) or untreated rats. All rats were necropsied at the termination of the study (week 32). T he incidences of tongue lesions (neoplasms and preneoplasms), polyamin e levels in the tongue tissue and cell proliferation activity estimate d by 5-bromodeoxyuridine (BrdU)-labelling index were compared among th e groups. In addition, the activities of gluthathione S-transferase (G ST) and quinone reductase (QR) in liver and tongue of rats gavaged var ious 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 initiatio n phase caused a significant reduction in the frequency of tongue carc inoma (100 ppm auraptene, 91% reduction, P < 0.001; 500 ppm auraptene, 63% reduction, P < 0.05). When fed auraptene after 4-NQO exposure, th e 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 sign ificantly smaller than those in carcinogen controls (P < 0.05). There were no pathological alterations in rats treated with 500 ppm aurapten e alone or those in an untreated control group. Dietary administration of auraptene significantly decreased BrdU-labelling index and polyami ne concentrations in the oral mucosa (P < 0.05). In addition, aurapten e 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 n eoplasms induced by 4-NQO. Thus, suppression by the initiation-feeding of auraptene might relate to elevation in the phase II enzymes GST an d QR of the liver and tongue, and inhibition occurring during the post -initiation might be related to suppression of increased cell prolifer ation caused by 4-NQO in the oral mucosa.