Chemoprevention of 4-Nitroquinoline 1-Oxide-induced Oral Carcinogenesis in Rats by Flavonoids Diosmin and Hesperidin, Each Alone and in Combination

Abstract The modifying effects of the two flavonoids diosmin and hesperidin given during the initiation and postinitiation phases of oral carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats. The compounds were tested alone and in combination. At 6 weeks of age, animals were divided into experimental and control groups and fed diets containing 1000 ppm diosmin and 1000 ppm hesperidin and a diet containing both compounds (900 ppm diosmin and 100 ppm hesperidin). At 7 weeks of age, all animals except those treated with each test chemical alone and control groups were given 4-NQO (20 ppm) in the drinking water for 8 weeks to induce oral cancer. Starting 7 days before the 4-NQO exposure, groups of animals were fed the diets containing test chemicals 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 containing diosmin, hesperidin, or diosmin combined with hesperidin and maintained on these diets for 22 weeks. The other groups consisted of rats given diosmin (1000 ppm), hesperidin (1000 ppm), and the combination regimen of these two compounds (900 ppm diosmin with 100 ppm hesperidin) alone, and untreated rats. All animals 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 a 5-bromodeoxyuridine-labeling index and by morphometric analysis of silver-stained nucleolar organizer regions protein were compared among the groups. Feeding of both compounds singly or in combination during the initiation phase caused a significant reduction in the frequency of tongue carcinoma [diosmin, 68% reduction ( P P P P P P P P P P