CHEMOPREVENTIVE EFFECTS OF DIOSMIN AND HESPERIDIN ON N-BUTYL-N-(4-HYDROXYBUTYL)NITROSAMINE-INDUCED URINARY-BLADDER CARCINOGENESIS IN MALE ICR MICE

The chemopreventive effects of 2 flavonoids (diosmin and hesperidin) o n N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary-bladd er 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 th e test compounds (group 2, 1000 ppm diosmin; group 3, 1000 ppm hesperi din; group 4,900 ppm diosmin + 100 ppm hesperidin) for 8 weeks during the initiation phase, while groups 5 to 7 were fed these diets, respec tively, 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 le sions and cell-proliferation activity estimated by enumeration of silv er-stained nucleolar-organizer-region-associated proteins (AgNORs) and by the 5-bromodeoxyuridine (BUdR)-labeling index was compared among t he groups, Feeding of the test compounds, singly or in combination, du ring both phases caused a significant reduction in the frequency of bl adder carcinoma and preneoplasia. Dietary administration of these comp ounds significantly decreased the AgNOR count and the BUdR-labeling in dex of various bladder lesions. These findings suggest that the flavon oids diosmin and hesperidin, individually and in combination, are effe ctive in inhibiting chemical carcinogenesis of the bladder, and that s uch inhibition might be partly related to suppression of cell prolifer ation. (C) 1997 Wiley-Liss, Inc.