Dietary eicosapentaenoic and docosahexaenoic acids decrease prostanoids in the ileum of rats treated with irinotecan and 5-fluorouracil

Abstract

BACKGROUND

Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are chemotherapeutic agents that disrupt the gastrointestinal tract. Prostanoids derived from arachidonic acid (AA) disrupt colonic water and electrolyte equilibrium and are implicated in chemotherapy-induced diarrhea. However, research assessing prostanoids in the ileum and effect of anti-inflammatory omega-3 polyunsaturated fatty acids are lacking.

AIM

To investigate effects of CPT-11 + 5-FU and dietary eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) on phospholipids and oxylipins in ileum tissue.

METHODS

Ward colon tumor was implanted and grew for approximately 2 weeks in Fischer rats fed a semi-purified standard diet prior to providing CPT-11 + 5-FU. On the same day as injecting CPT-11 (day 0), half of the rats were switched to a diet containing EPA and DHA. Rats were euthanized on day 0 (baseline) and following chemotherapy on days 2, 4, and 8 (n = 4-5/group).

RESULTS

CPT-11 + 5-FU increased oxylipins by day 2 derived from n-6 fatty acid (P = 0.002) and AA (P = 0.013), specifically 6-keto-prostaglandin (PG)-F_1α (P < 0.0001), 8-hydroxyeicosatetraenoic acid (P = 0.006), and leukotriene B4 (P = 0.024). Feeding EPA + DHA increased EPA and DHA in ileal phospholipid by 40-fold and 2-fold from baseline to day 8, respectively, corresponding with a 10-fold increase in EPA metabolites and a 2-fold increase in DHA metabolites. EPA metabolites 15-hydroxyeicosapentaenoic acid (HEPE), 18-HEPE, and 17,18-dihydroxy-eicosatetraenoic acid; DHA metabolite 16-hydroxydocosahexaenoic acid; and AA metabolite lipoxin A4 increased by day 8 in animals fed the EPA + DHA diet compared to the control diet while 6-keto-PGF_1α and PGD₂ decreased below baseline.

CONCLUSION

Dietary EPA and DHA are incorporated into ileal membrane phospholipid, counteracting the chemotherapy-induced proinflammatory oxylipin profile, disrupting synthesis of prostanoids, and increasing synthesis of anti-inflammatory oxylipins.

Keywords: Ileum; Oxylipins; Phospholipid fatty acids; Rat; Tumor; Chemotherapy; Colorectal cancer; N-3 fatty acids; Fish oil; Irinotecan

Core Tip: The present study is the first to investigate n-6- and n-3-derived oxylipin levels from ileum tissue after irinotecan + 5-fluorouracil and modification by dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The arachidonic acid (AA) metabolite 6-keto-prostaglandin F_1α implicated in inhibiting water absorption and electrolyte dysregulation increased after irinotecan + 5-fluorouracil. Dietary EPA and DHA markedly reduced 6-keto-prostaglandin F_1α and several other prostanoids while increasing protective and resolving mediators, lipoxin A₄ (AA-derived) and protectin-D1 (DHA-derived). Oxylipin potential to reduce the risk of chemotherapy-induced adverse effects, such as diarrhea, should be explored in models of multi-cycle chemotherapy.