Treatment of mice with 2,3,7,8-Tetrachlorodibenzo-p-dioxin markedly increases the levels of a number of cytochrome P450 metabolites of omega-3 polyunsaturated fatty acids in the liver and lung

Abstract

We previously reported that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increased the levels of several cytochrome P450 metabolites of the omega-6 polyunsaturated fatty acids (PUFAs), arachidonic acid (ARA) and linoleic acid in the serum, liver, lung and spleen of C57BL/6 mice in an aryl hydrocarbon receptor (AHR)-dependent fashion. These increases correlated with increased levels of CYP1A1, CYP1A2 and/or CYP1B1. In the current study, we measured 77 oxylipins, including 59 that we had not measured previously, and demonstrate that TCDD also markedly increases the levels of many epoxide and diol metabolites of the omega-3 PUFAs, α-linolenic acid, eicosapentaenoic acid (EPA) and docasahexaenoic acid (DHA) in these mice. Since these epoxide metabolites have been reported to have opposite effects on angiogenesis, tumor growth and tumor metastasis compared with the equivalent metabolites of omega-6 PUFA, these observations have important implications with regard to the potential involvement of the cytochrome P450 metabolites of PUFAs in mediating the biological effects of TCDD and other agonists of AHR.

Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin

“…Previously, it has been reported that TCDD significantly increases P450-generated metabolites of AA, 19-and 20-HETE, in the liver of male mice (Bui et al, 2012;Yang et al, 2013). Although TCDD induces CYP1A1, 1A2, and 1B1 and studies show they can produce 19-HETE, there is no evidence these P450s can produce 20-HETE (Choudhary et al, 2004;El-Sherbeni et al, 2014;Falck et al, 1990;Schwarz et al, 2004).…”

“…Specifically, we show that the TCDD-induced vascular dysfunction is mediated by a loss of vasodilation via increased oxidative stress. Recently, however, it has been shown that TCDD also increases cytochrome P450-dependent metabolites of arachidonic acid (AA,) that lead to vasoconstriction (Bui et al, 2012;Hankinson 2016;Yang et al, 2013). The potential impact of these vasoconstrictors to TCDD-induced vascular dysfunction has not been investigated.…”

Mining Gene Expression Data for Pollutants (Dioxin, Toluene, Formaldehyde) and Low Dose of Gamma-Irradiation

“…It is interesting to note altered metabolism of cytochrome P450 under the influence of dioxin and toluene in females and, to a lesser extent, in males. From previously published data, we know that 2,3,7,8-tetrachlorodibenzo-p-dioxin dose-dependently induces expression of cytochrome P450 isoforms [62]. CYP450s use electrons from their cofactors to catalyze activation of molecular oxygen, leading to substrate oxidation for different goals - steroid hormones synthesis, degradation of xenobiotics (organic toxins).…”

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

“…Although P450 2C8 and P450 2J2 are generally considered to be the major isoforms responsible for EET production, growing evidence indicates a role in the synthesis of the oxylipins by the inducible P450 1A1 and P450 1A2 (Nebert and Karp, 2008). The potent AhR agonist 2,3,7,8-tetrachlorodibenzodioxin (TCDD) for example, leads to increase epoxy and dihydroxy fatty acid concentrations in mammalian liver and lung (Yang et al, 2013). Furthermore, a number of AhR-activators including TCDD and OME increased levels of various epoxy and dihydroxy metabolites in chick embryos (Diani-Moore et al, 2006).…”