CITRUS AURAPTENE EXERTS DOSE-DEPENDENT CHEMOPREVENTIVE ACTIVITY IN RAT LARGE-BOWEL TUMORIGENESIS - THE INHIBITION CORRELATES WITH SUPPRESSION OF CELL-PROLIFERATION AND LIPID-PEROXIDATION AND WITH INDUCTION OF PHASE-II DRUG-METABOLIZING-ENZYMES

In our previous short-term experiment, Citrus auraptene inhibited the development of azoxymethane (AOM)-induced aberrant crypt foci, which a re precursor lesions for colorectal carcinoma. In the present study, t he possible inhibitory effect of dietary administration of auraptene w as investigated using an animal colon carcinogenesis model with a colo n carcinogen AOM. Male F344 rats were given s.c. injections of AOM (15 mg/kg body weight) once a week for 3 weeks to induce colon neoplasms. They also received diets containing 100 or 500 ppm auraptene for 4 we eks in groups of ''initation'' feeding, starting 1 week before the fir st dosing of AOM. The diets containing auraptene were also given to ra ts for 38 weeks in groups of ''postinitiation'' feeding. At the termin ation of the study (38 weeks), dietary administration of auraptene cau sed dose-dependent inhibition in AOM-induced large bowel carcinogenesi s. Auraptene feeding during the initiation phase reduced the incidence of colon adenocarcinoma by 49% at 100 ppm (P = 0.099) and 65% at 500 ppm (P = 0.0075). Auraptene administration during the postinitiation p hase inhibited the incidence of colon adenocarcinoma by 58% at 100 ppm (P = 0.021) and 65% at 500 ppm (P = 0.0075). Also, the multiplicity o f colon carcinoma was significantly reduced by initiation feeding at a dose level of 500 ppm (P < 0.01) and postinitiation feeding at a leve l of 100 and 500 ppm (P < 0.05 and P < 0.01, respectively). Feeding of auraptene suppressed the expression of cell proliferation biomarkers (ornithine decarboxylase activity and polyamine content) in the coloni c mucosa and reduced the production of aldehydic lipid peroxidation [m alondialdehyde and 4-hydroxy-2(E)-nonenal]. In addition, auraptene inc reased the activities of Phase II drug-metabolizing enzymes (glutathio ne S-transferase and quinone reductase) in the Liver and colon. These findings suggest that the inhibitory effects of auraptene on AOM-induc ed colon tumorigenesis at the initiation level might be associated, in part, with increased activity of Phase II enzymes, and those at the p ostinitiation stage might be related to suppression of cell proliferat ion and lipid peroxidation in the colonic mucosa.