Eicosapentaenoic acid inhibits the growth of liver preneoplastic lesions and alters membrane phospholipid composition and peroxisomal beta-oxidation.

The purpose of this study was to determine whether individual administration of highly purified eicosapentaenoic acid (EPA), one of the main components of the n-3 polyunsaturated fatty acid family, would alter the growth of focal lesions during hepatocarcinogenesis. The protocol used to induce chemical carcinogenesis in liver was the Solt-Farber model (diethylnitrosamine as initiator and 2-acetylaminofluorene and carbon tetrachloride associated with partial hepatectomy as promoters). Proliferative lesions were quantified with the histochemical marker gamma-glutamyltranspeptidase at partial hepatectomy and at sacrifice. The number and size of the gamma-glutamyltranspeptidase-positive foci observed were significantly lower in rats supplemented with EPA. Fatty acid treatment increased EPA and docosapentaenoic acid content in membrane total phospholipids, in phosphatidylethanolamine, and in phosphatidylcholine. The content of arachidonic acid decreased significantly only in total phospholipids and in phosphatidylethanolamine. Fatty acid content of phosphatidylinositol was not modified. Moreover, we observed an increase in the activity of palmitoyl-CoA oxidase, the limiting enzyme of peroxisomal beta-oxidation, the preferential metabolic pathway of n-3 polyunsaturated fatty acid. Conversely, unmodified levels of alpha-tocopherol and unchanged production of lipid peroxidation products (malondialdehyde) were observed. These results suggest that the EPA inhibitory effect on preneoplastic foci development may be related to alteration of fatty acid composition in phospholipid classes and to enhancement of peroxisomal beta-oxidation and H2O2 production.

Cell proliferation, differentiation, and apoptosis are modified by n-3 polyunsaturated fatty acids in normal colonic mucosa.

Supplementation with low doses of eicosapentaenoic (EPA) or docosahexaenoic (DHA) acid was used here to investigate changes in epithelial proliferation, differentiation, and apoptosis in normal rat colonic mucosa. ACI/T rats received by oral administration low doses of purified EPA or DHA ethyl esters (1 g/kg body weight) and colonic mucosa was analyzed for cell proliferation, differentiation, and apoptosis. n-3 Polyunsaturated fatty acid incorporation into membrane phospholipids was investigated as reflections of fatty acid metabolism. Both EPA and DHA suppressed colonocyte proliferation and increased the numbers of differentiating and apoptotic cells without modification of the crypt morphology and the number of cells per crypt columns. A significant incorporation of the supplemented fatty acids into total phospholipids was observed. This enrichment was accompanied by a decreased content in arachidonic acid. The observation that EPA and DHA do not alter crypt morphology although they modify cell turnover in normal colonic mucosa suggests a possible use of these fatty acids as dietary chemopreventive agents.

Dietary supplementation with eicosapentaenoic and docosahexaenoic acid inhibits growth of Morris hepatocarcinoma 3924A in rats: effects on proliferation and apoptosis.

The effect of individual administration of low doses of highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (1 g/kg body weight) on the growth of Morris hepatocarcinoma 3924A transplanted in ACI/T rats was investigated. Both EPA and DHA inhibited growth of the hepatocarcinoma (50% reduction of tumor weight or volume at the 19th day after transplantation for both of the n-3 PUFA groups). EPA treatment reduced the percentage of proliferating tumor cells labeled with BUdR (10-fold), whereas DHA did not. Conversely, DHA supplementation induced a doubling of the number of cells undergoing apoptosis (labeled by TUNEL), whereas EPA treatment was much less effective. Analysis of changes in phospholipid fatty acids in tumor-cell membranes after both treatments with EPA and DHA showed a significant reduction in arachidonic-acid levels. EPA and docosapentaenoic acid (DPA), its elongation product, were increased in the phospholipids from EPA-treated animals. DHA and EPA, but not DPA, were increased in the DHA-treated group. It is concluded from the results of the present study that the anti-tumoral effect of EPA is related mainly to its inhibition of cell proliferation, whereas that of DHA corresponds with its induction of apoptosis. The alterations in fatty-acid composition induced by EPA or DHA appear to be factors underlying their differential actions on cell proliferation and apoptosis.