Detoxification Cytochrome P450s (CYPs) in Families 1–3 Produce Functional Oxylipins from Polyunsaturated Fatty Acids

Abstract

This manuscript reviews the CYP-mediated production of oxylipins and the current known function of these diverse set of oxylipins with emphasis on the detoxification CYPs in families 1–3. Our knowledge of oxylipin function has greatly increased over the past 3–7 years with new theories on stability and function. This includes a significant amount of new information on oxylipins produced from linoleic acid (LA) and the omega-3 PUFA-derived oxylipins such as α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). However, there is still a lack of knowledge regarding the primary CYP responsible for producing specific oxylipins, and a lack of mechanistic insight for some clinical associations between outcomes and oxylipin levels. In addition, the role of CYPs in the production of oxylipins as signaling molecules for obesity, energy utilization, and development have increased greatly with potential interactions between diet, endocrinology, and pharmacology/toxicology due to nuclear receptor mediated CYP induction, CYP inhibition, and receptor interactions/crosstalk. The potential for diet-diet and diet-drug/chemical interactions is high given that these promiscuous CYPs metabolize a plethora of different endogenous and exogenous chemicals.

Increased Perfluorooctanesulfonate (PFOS) Toxicity and Accumulation Is Associated with Perturbed Prostaglandin Metabolism and Increased Organic Anion Transport Protein (OATP) Expression

“…Reductions in CYP-derived oxylipins are consistent with inflammatory conditions [ 35 , 36 ]. All of the other oxylipin metabolites that were inversely associated (reduced in concentration) with increasing PFOS concentrations were epoxides, suggesting that epoxide hydrolase activity was induced by PFOS treatment in the females and, in turn, dihydroxy-oxylipins were produced [ 12 , 37 ].…”

“…For example, 19,20-EpDPA is decreased possibly due to the induction of epoxide hydrolases, and is lower in 1-PFOS-treated hCYP2B6-Tg that show less steatosis than Cyp2b-null mice ( Figure 2 ). Previous research has shown that 19,20-EpDPA is inversely associated with hepatocyte lipid accumulation [ 12 , 77 ]. 9,10-DiHOME, which was induced by PFOS, stimulates adipogenesis through PPARγ [ 78 ].…”

“…CYP2B6 is a cytochrome P450 enzyme that is primarily expressed in the liver and metabolizes many different chemicals, including xenobiotics such as various pesticides, plasticizers, and several pharmaceuticals, steroids such as testosterone and estradiol, and polyunsaturated fatty acids such as linoleic acid (LA), arachidonic acid (AA), and docosahexaenoic acid (DHA) [ 11 , 12 , 13 , 14 , 15 ]. Several PUFA metabolites (oxylipins) are associated with high-fat diet-induced steatosis in hCYP2B6-Tg mice, including 14,15-EET, PGF2a, 9-HODE, and 13-KODE, and to a lesser extent, 11,12-EET, 14,15-DHET, and 9,10-DiHOME.…”

“…Some lipid metabolites may prove to be reasonable biomarkers of PFOS-mediated steatosis or non-alcoholic fatty liver disease (NAFLD). Recent studies indicate that oxylipins may prove to be biomarkers of age, Alzheimer’s, cardiovascular disease, inflammation, and toxicant exposure such as dioxin and PFAS [ 12 , 16 , 17 , 18 , 19 ].…”

Influence of 2 Weeks of Mango Ingestion on Inflammation Resolution after Vigorous Exercise

“…Oxylipin generation is a highly controlled process that is sensitive to both nutrition- and exercise-based interventions [ 51 , 52 ]. More than 50 enzymes are involved in producing oxylipins, and signaling is conducted by binding to a variety of receptors or by interacting with intracellular pathways [ 52 , 53 , 54 ]. The enzymes that regulate oxylipin production and the receptors to which they bind are potential targets for metabolites derived from dietary macronutrients and polyphenols [ 9 , 10 , 11 , 12 , 13 , 14 , 54 ].…”