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Review
. 2016 Aug;48(3):342-50.
doi: 10.1080/03602532.2016.1197240. Epub 2016 Jun 30.

The role of AHR-inducible cytochrome P450s in metabolism of polyunsaturated fatty acids

Affiliations
Review

The role of AHR-inducible cytochrome P450s in metabolism of polyunsaturated fatty acids

Oliver Hankinson. Drug Metab Rev. 2016 Aug.

Abstract

The environmental pollutant 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) is the prototype of a large number of non-genotoxic carcinogens, dietary phytochemicals and endogenous metabolites that act via binding the aryl hydrocarbon receptor (AHR). The TCDD-liganded AHR massively upregulates CYP1A1, CYP1A2 and CYP1B1 in many mammalian organs. We demonstrated that TCDD treatment markedly increases the levels of several epoxides and diol metabolites of the epoxides of both ω-6 and ω-3 polyunsaturated fatty acids (PUFA) in the liver and lungs of mice, in an aryl hydrocarbon receptor-dependent fashion, and most likely via the activities of the CYP1 family members. ω-6 Epoxides are known to stimulate tumor growth, angiogenesis, and metastasis in mice. Interestingly, ω-3 epoxides have the opposite effect on these parameters. TCDD and other AHR agonists may, therefore, impact angiogenesis, growth and metastasis of tumors in either a positive or negative way, depending on the relative levels of ω -6 epoxides and ω-3 epoxides generated in the host and/or tumor cells. This is of potential relevance to carcinogenesis by AHR agonists in the human, since the human population is exposed to widely varying ω-6: ω-3 PUFA ratios in the diet.

Keywords: 2,3,7,8-Tetrachlorodibenzo-ρ-dioxin (TCDD); CYP1; aryl hydrocarbon receptor (AHR); eicosanoid; metastasis; omega-3 (ω-3) PUFA; omega-6 (ω-6) PUFA; oxylipin; polyunsaturated fatty acids (PUFA); tumor growth.

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Figures

Figure 1
Figure 1
The metabolism of arachidonic acid.
Figure 2
Figure 2
Heat map summarizing the changes in oxylipin levels elicited by TCDD in mice. Each square represents a different metabolite measured in three or more TCDD-treated or TCDD-untreated male mice.

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