Epoxy-Oxylipins and Soluble Epoxide Hydrolase Metabolic Pathway as Targets for NSAID-Induced Gastroenteropathy and Inflammation-Associated Carcinogenesis

Polyunsaturated fatty acids (PUFAs) including epoxide-modified -3 and -6 fatty acids are made via oxidation to create highly polarized carbon-oxygen bonds crucial to their function as signaling molecules. A critical PUFA, arachidonic acid (ARA), is metabolized to a diverse set of lipids signaling molecules through cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 epoxygenase, or cytochrome P450 hydroxylase, however the majority of ARA is metabolized into anti-inflammatory epoxides via cytochrome P450 enzymes. These short-lived epoxide lipids are rapidly metabolized or inactivated by the soluble epoxide hydrolase (sEH) into diol-containing products. sEH inhibition or knockout has been a practical approach to study the biology of the epoxide lipids, and has been shown to effectively treat inflammatory conditions in the preclinical models including gastrointestinal ulcers and colitis by shifting oxylipins to epoxide profiles, inhibiting inflammatory cell infiltration and activation, and enhancing epithelial cell defense via increased mucin production, thus providing further evidence for the role of sEH as a pro-inflammatory protein. Non-steroidal anti-inflammatory drugs (NSAIDs) with COX-inhibitor activity are among the most commonly used analgesics and have demonstrated applications in the management of cardiovascular disease and intriguingly cancer. Major side effects of NSAIDs however are gastrointestinal ulcers which frequently precludes their long-term applica...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research