Chemopreventive effects of diosmin and hesperidin onN-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in male ICR mice

Abstract

The chemopreventive effects of 2 flavonoids (diosmin and hesperidin) on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary-bladder carcinogenesis were examined in male ICR mice. Animals were divided into 11 groups, and groups 1 to 7 were given OH-BBN (500 ppm) in the drinking water for 6 weeks. Groups 2 to 4 were fed diets containing the test compounds (group 2, 1000 ppm diosmin; group 3, 1000 ppm hesperidin; group 4,900 ppm diosmin + 100 ppm hesperidin) for 8 weeks during the initiation phase, while groups 5 to 7 were fed these diets, respectively, for 24 weeks during the post-initiation phase. Groups 8 to 11 were controls, given only the test compounds or untreated basal diets throughout the experiment (weeks 1 to 32). The incidence of bladder lesions and cell-proliferation activity estimated by enumeration of silver-stained nucleolar-organizer-region-associated proteins (AgNORs) and by the 5-bromodeoxyuridine (BUdR)-labeling index was compared among the groups. Feeding of the test compounds, singly or in combination, during both phases caused a significant reduction in the frequency of bladder carcinoma and preneoplasia. Dietary administration of these compounds significantly decreased the AgNOR count and the BUdR-labeling index of various bladder lesions. These findings suggest that the flavonoids diosmin and hesperidin, individually and in combination, are effective in inhibiting chemical carcinogenesis of the bladder, and that such inhibition might be partly related to suppression of cell proliferation.