Dietary EPA+DHA Mitigate Hepatic Toxicity and Modify the Oxylipin Profile in an Animal Model of Colorectal Cancer Treated with Chemotherapy

SIMPLE SUMMARY: Liver toxicity as a result of chemotherapy for metastatic colorectal cancer is common, but it remains poorly understood. The bioactive metabolites of polyunsaturated fatty acids, oxylipins, and pro-inflammatory cytokines play crucial roles in numerous biological processes and pathological conditions. A preclinical model of colorectal cancer treated with chemotherapy was used to understand the alterations of oxylipins and cytokines concurrently with the alterations of the liver pathology and to test whether liver toxicity can be modified by a diet containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oil. After chemotherapy, the measures of liver toxicity were evident and were associated with the elevation of specific oxylipins and cytokines. Dietary fish oil influenced oxylipin and cytokine production while mitigating liver toxicity after chemotherapy treatment. Fish oil may present a novel dietary strategy to attenuate liver toxicity during chemotherapy. ABSTRACT: Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are commonly used to treat metastatic colorectal cancer, but chemotherapy-associated steatosis/steatohepatitis (CASSH) frequently accompanies their use. The objective of this study was to determine effect of CPT-11+5-FU on liver toxicity, liver oxylipins, and cytokines, and to explore whether these alterations could be modified by dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oil (EPA+DHA). Tumor-bearing animals were administered CPT-11+5-FU and maintained on a control diet or a diet containing EPA+DHA (2.3 g/100 g). Livers were collected one week after chemotherapy for the analysis of oxylipins, cytokines, and markers of liver pathology (oxidized glutathione, GSSH; 4-hydroxynonenal, 4-HNE, and type-I collagen fiber). Dietary EPA+DHA prevented the chemotherapy-induced increases in liver GSSH (p < 0.011) and 4-HNE (p < 0.006). Compared with the tumor-bearing animals, ten oxylipins were altered (three/ten n-6 oxylipins were elevated while seven/ten n-3 oxylipins were reduced) following chemotherapy. Reductions in the n-3 fatty-acid-derived oxylipins that were evident following chemotherapy were restored by dietary EPA+DHA. Liver TNF-α, IL-6 and IL-10 were elevated (p < 0.05) following chemotherapy; dietary EPA+DHA reduced IL-6 (p = 0.09) and eotaxin (p = 0.007) levels. Chemotherapy-induced liver injury results in distinct alterations in oxylipins and cytokines, and dietary EPA+DHA attenuates these pathophysiological effects.