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 studied using a multiorgan carcinogenesis model in male rats. Rats were treated with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-4-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and dihydroxy-di-n-propylnitrosamine (DHPN) during the first 7 weeks, and then given unsaturated fatty acid (UFAs), docosahexaenoic acid (n-3, C_22:6) (DHA), eicosapentaenoic acid (n-3, C_20:5) (EPA), linoleic acid (n-6, C_18:2) (LA) or oleic acid (n-9, C_18:1) (OA) at a dose of 1.0 ml/rat, 3 times a week by gavage for the consecutive 30 weeks. All rats were fed a low LA basal diet throughout the experiment and a calorie-restricted basal diet during the period of UFAs feeding administration. DHA significantly reduced tumor size and numbers 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 other hand, LA showed a tendency to inhibit lung carcinogenesis, but to promote large intestinal carcinogenesis. However these UFAs did not influence preneoplastic and neoplastic lesion development in the liver, kidney, and urinary bladder. Levels of the administered fatty acids were clearly increased 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 data thus provide evidence that an organotropism exists with regard to the influence of UFAs on carcinogenesis, which correlates with reduction of tissue AA levels in the target organs.