Organotropic chemopreventive effects of n-3 unsaturated fatty acids in a rat multi-organ carcinogenesis model

Organotropic chemopreventive effects of n-3 unsaturated fatty acids were st udied using a multiorgan carcinogenesis model in male rats. Rats were treat ed with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-4 -hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and dihydroxy-d i-n-propylnitrosamine (DHPN) during the first 7 weeks, and then given unsat urated fatty acid (UFAs), docosahexaenoic acid (n-3, C-22:6) (DHA), eicosap entaenoic acid (n-3, C-20:5) (EPA), linoleic acid (n-6, C-18:2) (LA) or ole ic acid (n-9, C-18:1) (OA) at a dose of 1.0 ml/rat, 3 times a week by gavag e for the consecutive 30 weeks. All rats were fed a low LA basal diet throu ghout the experiment and a calorie-restricted basal diet during the period of UFAs feeding administration. DHA significantly reduced tumor size and nu mbers in the large intestine as compared to OA treatment. Furthermore, DHA showed a tendency to inhibit carcinogenesis in the small intestine and lung . EPA also showed a tendency to inhibit intestinal carcinogenesis. On the o ther hand, LA showed a tendency to inhibit lung carcinogenesis, but to prom ote large intestinal carcinogenesis. However these UFAs did not influence p reneoplastic and neoplastic lesion development in the liver, kidney, and ur inary bladder. Levels of the administered fatty acids were clearly increase d in the serum and organs. In contrast, arachidonic acid (AA) levels in the large and small intestines and liver were markedly decreased by treatment with DHA and EPA. Decreased levels of AA in the large intestine correlated well with tumor incidence, although the number of glutathione S-transferase -positive (GST-P+) foci showed an inverse correlation with AA levels. The d ata thus provide evidence that an organotropism exists with regard to the i nfluence of UFAs on carcinogenesis, which correlates with reduction of tiss ue AA levels in the target organs.