Endogenous Functions of the Aryl Hydrocarbon Receptor (AHR): Intersection of Cytochrome P450 1 (CYP1)-metabolized Eicosanoids and AHR Biology

The AHR, 2The abbreviations used are: AHRaryl hydrocarbon receptorXTFsxenosensor transcription factorsALOXarachidonate lipoxygenaseCYPcytochrome P450PDVpatent ductus venosusAVarteriovenousGIgastrointestinal a ligand-activated transcription factor, was first identified indirectly in the 1970s; the mouse and human genes were cloned in the early 1990s. Molecular mechanisms and biological consequences of AHR-mediated regulation of mammalian cytochrome P450 enzymes by foreign chemicals (e.g. polycyclic aromatic hydrocarbons and dioxins) have been studied extensively. Binding of such ligands to AHR leads to transcriptional activation of CYP1A1, CYP1A2, and CYP1B1; in turn, these enzymes catalyze oxidative detoxication or activation of most ligands. From the start, AHR endogenous ligands and functions were postulated; although this was initially controversial, the robust phenotype of Ahr–/– knock-out mice provided clear evidence of physiological roles (and endogenous ligands) for AHR. AHR has numerous important endogenous functions: during conception and embryonic and fetal development; in the immune, cardiovascular, neural, and reproductive systems; and in hepatocytes, skin cells, and adipocytes. These myriad AHR-mediated processes mirror the vast universe of action of the eicosanoids, lipid mediators known to undergo cytochrome P450-dependent oxidation. We propose that many endogenous and exogenous cellular stimuli lead to (i) AHR-dependent CYP1-dependent eicosanoid synthesis and degradation and (ii) AHR-dependent CYP1-independent (eicosanoid-dependent and -independent) responses. These two pathways can be delineated from one another in genetic models: the former is absent in the recently characterized Cyp1a1/1a2/1b1–/– triple-knock-out mouse, and the latter is absent in the Ahr–/– knock-out mouse. Identification of specific eicosanoids whose synthesis or degradation is carried out by each CYP1 enzyme should allow for identification of physiological endogenous AHR ligands. (For "History and Background," see supplemental material (Box 1).) aryl hydrocarbon receptor xenosensor transcription factors arachidonate lipoxygenase cytochrome P450 patent ductus venosus arteriovenous gastrointestinal Oxygenated fatty acids are widely employed as signaling molecules by prokaryotes and eukaryotes (1Tsitsigiannis D.I. Keller N.P. Trends Microbiol. 2007; 15: 109-118Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). Among these, the eicosanoids are bioactive oxygenated derivatives of ω-6 or ω-3 essential fatty acids. Although the first identified eicosanoids were derived from fatty acids with 20 carbon atoms (hence, "eicosa," Greek for "twenty"), such as arachidonic acid, eicosapentaenoic acid, and dihomo-γ-linolenic acid, related derivatives of 22-carbon atom essential fatty acids (e.g. docosahexaenoic acid) carry the same moniker. Eicosanoids are local hormones released by most vertebrate (and some invertebrate) cells, which act in autocrine or paracrine fashion and then become rapidly inactivated. Potent in the nanomolar range, at least 13 categories of eicosanoids have been classified to date (supplemental Table S2), and if one includes all possible stereoisomers, the total number of eicosanoids now exceeds 150. Supplemental Table S2 lists the incredibly large number of critical life functions mediated via eicosanoids, showing some degree of specificity of function among the 13 categories. In terms of immunity, both initiation and resolution of inflammatory processes are under the critical control of eicosanoids (2Serhan C.N. Annu. Rev. Immunol. 2007; 25: 101-137Crossref PubMed Scopus (829) Google Scholar). Generally, eicosanoids are not stored within cells but are synthesized as needed; one exception is that red blood cells are reservoirs for cis- and trans-epoxyeicosatrienoic acids that can quickly be released (3Jiang H. Prostaglandins Other Lipid Mediat. 2007; 82: 4-10Crossref PubMed Scopus (9) Google Scholar). Stimuli that initiate eicosanoid biosynthesis and release include mechanical trauma, cytokines, growth factors, xenobiotics, and even other eicosanoids. Such stimuli trigger the activation of phospholipases at the cell or nuclear membrane, where fatty acid precursors of eicosanoids are incorporated as esters into larger molecules (phospholipids and diacylglycerol), whereupon the phospholipase catalyzes ester hydrolysis of phospholipid (via phospholipase A2) or diacylglycerol (via diacylglycerol lipase). The rate-limiting step for eicosanoid formation appears to be this hydrolysis, which frees eicosanoid precursors. Eicosanoids exert complex control over virtually all life functions (supplemental Table S2). Interestingly, the list of processes that exhibit abnormalities when AHR is absent or are modulated by activation of AHR (supplemental Table S1) is quite similar to the list of eicosanoid-mediated functions (supplemental Table S2). Generic Signals and Responses—Any of thousands of different exogenous signals affecting a cell can be viewed as a stimulus that is "perceived" by XTFs; these include the AHR, constitutive androstane receptor, hepatocyte nuclear factor, forkhead box, liver X receptor, peroxisome proliferator-activated receptor, farnesoid X receptor, pregnane X receptor, and related families (Fig. 1A), which then regulate various downstream targets. The concept of xenobiotic-related transporters and XTFs has been recently reviewed (4Nebert D.W. Dalton T.P. Nat. Rev. Cancer. 2006; 6: 947-960Crossref PubMed Scopus (742) Google Scholar). We envision the downstream events to include CYP1-, CYP2-, CYP3-, and CYP4-mediated synthesis and degradation of specific eicosanoids (5Nebert D.W. Russell D.W. Lancet. 2002; 360: 1155-1162Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar) as well as responses that are independent of these enzymes (Fig. 1A). AHR Signaling and Responses—Although AHR binds to AHR response elements in hundreds of genes throughout the genome, the three CYP1 genes conserved in all mammals (CYP1A1, CYP1A2, and CYP1B1) are both among the most highly induced of the panel of AHR-activated genes and central to the oxidative metabolism of many AHR ligands. Hence, we envision that signals received by AHR lead to downstream events (Fig. 1, B and C), which include AHR-dependent CYP1-dependent synthesis and degradation of specific eicosanoids and AHR-dependent CYP1-independent (eicosanoid-dependent and -independent) responses. Cyclooxygenases and ALOXs—Although considerable emphasis has been placed on the role of cyclooxygenase-1 and -2 and the ALOXs in eicosanoid synthesis and degradation (Fig. 1C), it has been experimentally demonstrated that dozens of members of the CYP1, CYP2, CYP3, and CYP4 families also participate in these processes (Table 1) (5Nebert D.W. Russell D.W. Lancet. 2002; 360: 1155-1162Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar). Every member of these four CYP families might be involved in eicosanoid metabolism, perhaps with redundancy (5Nebert D.W. Russell D.W. Lancet. 2002; 360: 1155-1162Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar). Pursuant to the present review about AHR endogenous functions, the precise steps catalyzed by CYP1A1, CYP1A2, and CYP1B1 remain to be demonstrated. In fact, the large number, complexity of pathways, extreme lability, and similarity of the various eicosanoid chemical structures and stereoisomers all contribute to the difficulty of successful research in this arena.TABLE 1Specific catalytic evidence for eicosanoid metabolism by members of the vertebrate CYP1, CYP2, CYP3, and CYP4 familiesCYP subfamily and eicosanoid categoriesRef.CYP1A Prostaglandins30Holm K.A. Park S.S. Gelboin H.V. Kupfer D. Arch. Biochem. Biophys. 1989; 269: 664-677Crossref PubMed Scopus (7) Google Scholar, 33Plastaras J.P. Guengerich F.P. Nebert D.W. Marnett L.J. J. Biol. Chem. 2000; 275: 11784-11790Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Arachidonic acid, prostaglandins31Tanaka S. Imaoka S. Kusunose E. Kusunose M. Maekawa M. Funae Y. Biochim. Biophys. Acta. 1990; 1043: 177-181Crossref PubMed Scopus (40) Google Scholar EETs, HETEs32Rifkind A.B. Lee C. Chang T.K. Waxman D.J. Arch. Biochem. Biophys. 1995; 320: 380-389Crossref PubMed Scopus (219) Google Scholar, 35Labitzke E.M. Diani-Moore S. Rifkind A.B. Arch. Biochem. Biophys. 2007; 468: 70-81Crossref PubMed Scopus (12) Google Scholar Arachidonic acid, EETs, eicosapentaenoic acid34Schwarz D. Kisselev P. Ericksen S.S. Szklarz G.D. Chernogolov A. Honeck H. Schunck W.H. Roots I. Biochem. Pharmacol. 2004; 67: 1445-1457Crossref PubMed Scopus (120) Google Scholar Eicosapentaenoic and docosahexaenoic acids36Fer M. Dreano Y. Lucas D. Corcos L. Salaun J.P. Berthou F. Amet Y. Arch. Biochem. Biophys. 2008; 471: 116-125Crossref PubMed Scopus (124) Google ScholarCYP1B EETs, HETEs37Choudhary D. Jansson I. Stoilov I. Sarfarazi M. Schenkman J.B. Drug Metab. Dispos. 2004; 32: 840-847Crossref PubMed Scopus (166) Google ScholarCYP2A Arachidonic acid, prostaglandins31Tanaka S. Imaoka S. Kusunose E. Kusunose M. Maekawa M. Funae Y. Biochim. Biophys. Acta. 1990; 1043: 177-181Crossref PubMed Scopus (40) Google ScholarCYP2B Arachidonic acid, prostaglandins31Tanaka S. Imaoka S. Kusunose E. Kusunose M. Maekawa M. Funae Y. Biochim. Biophys. Acta. 1990; 1043: 177-181Crossref PubMed Scopus (40) Google Scholar HPETEs38Chang M.S. Boeglin W.E. Guengerich F.P. Brash A.R. Biochemistry. 1996; 35: 464-471Crossref PubMed Scopus (50) Google Scholar EETs, HETEs39Keeney D.S. Skinner C. Travers J.B. Capdevila J.H. Nanney L.B. King Jr., L.E. Waterman M.R. J. Biol. Chem. 1998; 273: 32071-32079Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar EETs40Du L. Yermalitsky V. Ladd P.A. Capdevila J.H. Mernaugh R. Keeney D.S. Arch. Biochem. Biophys. 2005; 435: 125-133Crossref PubMed Scopus (24) Google Scholar, 41Du L. Yermalitsky V. Hachey D.L. Jagadeesh S.G. Falck J.R. Keeney D.S. J. Pharmacol. Exp. Ther. 2006; 316: 371-379Crossref PubMed Scopus (9) Google ScholarCYP2C Arachidonic acid, prostaglandins31Tanaka S. Imaoka S. Kusunose E. Kusunose M. Maekawa M. Funae Y. Biochim. Biophys. Acta. 1990; 1043: 177-181Crossref PubMed Scopus (40) Google Scholar Arachidonic acid42Imaoka S. Wedlund P.J. Ogawa H. Kimura S. Gonzalez F.J. Kim H.Y. J. Pharmacol. Exp. Ther. 1993; 267: 1012-1016PubMed Google Scholar EETs, HETEs32Rifkind A.B. Lee C. Chang T.K. Waxman D.J. Arch. Biochem. Biophys. 1995; 320: 380-389Crossref PubMed Scopus (219) Google Scholar Prostaglandins43Oliw E.H. Stark K. Bylund J. Biochem. Pharmacol. 2001; 62: 407-415Crossref PubMed Scopus (25) Google Scholar EETs44Michaelis U.R. Falck J.R. Schmidt R. Busse R. Fleming I. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 321-326Crossref PubMed Scopus (63) Google ScholarCYP2D Arachidonic acid, HETEs45Thompson C.M. Capdevila J.H. Strobel H.W. J. Pharmacol. Exp. Ther. 2000; 294: 1120-1130PubMed Google Scholar, 46Miyata N. Taniguchi K. Seki T. Ishimoto T. Sato-Watanabe M. Yasuda Y. Doi M. Kametani S. Tomishima Y. Ueki T. Sato M. Kameo K. Br. J. Pharmacol. 2001; 133: 325-329Crossref PubMed Scopus (170) Google ScholarCYP2E Arachidonic acid, prostaglandins31Tanaka S. Imaoka S. Kusunose E. Kusunose M. Maekawa M. Funae Y. Biochim. Biophys. Acta. 1990; 1043: 177-181Crossref PubMed Scopus (40) Google Scholar Arachidonic acid, EETs, HETEs47Laethem R.M. Balazy M. Falck J.R. Laethem C.L. Koop D.R. J. Biol. Chem. 1993; 268: 12912-12918Abstract Full Text PDF PubMed Google Scholar EETs, HETEs32Rifkind A.B. Lee C. Chang T.K. Waxman D.J. Arch. Biochem. Biophys. 1995; 320: 380-389Crossref PubMed Scopus (219) Google Scholar Prostaglandins33Plastaras J.P. Guengerich F.P. Nebert D.W. Marnett L.J. J. Biol. Chem. 2000; 275: 11784-11790Abstract Full Text Full Text PDF PubMed Scopus (68) Google ScholarCYP2J EETs48Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1024) Google Scholar, 51Jiang J.G. Chen C.L. Card J.W. Yang S. Chen J.X. Fu X.N. Ning Y.G. Xiao X. Zeldin D.C. Wang D.W. Cancer Res. 2005; 65: 4707-4715Crossref PubMed Scopus (238) Google Scholar Arachidonic acid, HETEs49Qu W. Bradbury J.A. Tsao C.C. Maronpot R. Harry G.J. Parker C.E. Davis L.S. Breyer M.D. Waalkes M.P. Falck J.R. Chen J. Rosenberg R.L. Zeldin D.C. J. Biol. Chem. 2001; 276: 25467-25479Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Arachidonic acid50King L.M. Ma J. Srettabunjong S. Graves J. Bradbury J.A. Li L. Spiecker M. Liao J.K. Mohrenweiser H. Zeldin D.C. Mol. Pharmacol. 2002; 61: 840-852Crossref PubMed Scopus (131) Google ScholarCYP2P Arachidonic acid, EETs, HETEs52Oleksiak M.F. Wu S. Parker C. Qu W. Cox R. Zeldin D.C. Stegeman J.J. Arch. Biochem. Biophys. 2003; 411: 223-234Crossref PubMed Scopus (31) Google ScholarCYP2U Arachidonic acid53Chuang S.S. Helvig C. Taimi M. Ramshaw H.A. Collop A.H. Amad M. White J.A. Petkovich M. Jones G. Korczak B. J. Biol. Chem. 2004; 279: 6305-6314Abstract Full Text Full Text PDF PubMed Scopus (144) Google ScholarCYP2W Arachidonic acid54Wu Z.L. Sohl C.D. Shimada T. Guengerich F.P. Mol. Pharmacol. 2006; 69: 2007-2014Crossref PubMed Scopus (90) Google ScholarCYP3A Arachidonic acid, prostaglandins31Tanaka S. Imaoka S. Kusunose E. Kusunose M. Maekawa M. Funae Y. Biochim. Biophys. Acta. 1990; 1043: 177-181Crossref PubMed Scopus (40) Google Scholar Prostaglandins33Plastaras J.P. Guengerich F.P. Nebert D.W. Marnett L.J. J. Biol. Chem. 2000; 275: 11784-11790Abstract Full Text Full Text PDF PubMed Scopus (68) Google ScholarCYP4A Prostaglandins43Oliw E.H. Stark K. Bylund J. Biochem. Pharmacol. 2001; 62: 407-415Crossref PubMed Scopus (25) Google Scholar, 55Aoyama T. Hardwick J.P. Imaoka S. Funae Y. Gelboin H.V. Gonzalez F.J. J. Lipid Res. 1990; 31: 1477-1482Abstract Full Text PDF PubMed Google Scholar Prostaglandins, arachidonic acid56Aitken A.E. Roman L.J. Loughran P.A. de la G.M. Masters B.S. Arch. Biochem. Biophys. 2001; 393: 329-338Crossref PubMed Scopus (12) Google Scholar EETs11Cowart L.A. Wei S. Hsu M.H. Johnson E.F. Krishna M.U. Falck J.R. Capdevila J.H. J. Biol. Chem. 2002; 277: 35105-35112Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar HETEs57Muller D.N. Schmidt C. Barbosa-Sicard E. Wellner M. Gross V. Hercule H. Markovic M. Honeck H. Luft F.C. Schunck W.H. Biochem. J. 2007; 403: 109-118Crossref PubMed Scopus (136) Google ScholarCYP4B HETEs58Mezentsev A. Mastyugin V. Seta F. Ashkar S. Kemp R. Reddy D.S. Falck J.R. Dunn M.W. Laniado-Schwartzman M. J. Pharmacol. Exp. Ther. 2005; 315: 42-50Crossref PubMed Scopus (22) Google Scholar, 59Seta F. Patil K. Bellner L. Mezentsev A. Kemp R. Dunn M.W. Schwartzman M.L. Prostaglandins Other Lipid Mediat. 2007; 84: 116-127Crossref PubMed Scopus (34) Google ScholarCYP4F Leukotrienes, prostaglandins60Kawashima H. Kusunose E. Thompson C.M. Strobel H.W. Arch. Biochem. Biophys. 1997; 347: 148-154Crossref PubMed Scopus (68) Google Scholar Leukotrienes61Kikuta Y. Kasyu H. Kusunose E. Kusunose M. Arch. Biochem. Biophys. 2000; 383: 225-232Crossref PubMed Scopus (22) Google Scholar Prostaglandins43Oliw E.H. Stark K. Bylund J. Biochem. Pharmacol. 2001; 62: 407-415Crossref PubMed Scopus (25) Google Scholar, 62Bylund J. Hidestrand M. Ingelman-Sundberg M. Oliw E.H. J. Biol. Chem. 2000; 275: 21844-21849Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 63Bylund J. Oliw E.H. Arch. Biochem. Biophys. 2001; 389: 123-129Crossref PubMed Scopus (9) Google Scholar Arachidonic acid64Stark K. Schauer L. Sahlen G.E. Ronquist G. Oliw E.H. Basic Clin. Pharmacol. Toxicol. 2004; 94: 177-183Crossref PubMed Scopus (26) Google Scholar Leukotrienes, lipoxins, HETEs65Kalsotra A. Turman C.M. Kikuta Y. Strobel H.W. Toxicol. Appl. Pharmacol. 2004; 199: 295-304Crossref PubMed Scopus (74) Google Scholar EETs66Le Quere V. Plee-Gautier E. Potin P. Madec S. Salaun J.P. J. Lipid Res. 2004; 45: 1446-1458Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Eicosapentaenoic and docosahexaenoic acids67Harmon S.D. Fang X. Kaduce T.L. Hu S. Raj G.V. Falck J.R. Spector A.A. Prostaglandins Leukot. Essent. Fatty Acids. 2006; 75: 169-177Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Lipoxins, HETEs68Kalsotra A. Anakk S. Brommer C.L. Kikuta Y. Morgan E.T. Strobel H.W. Arch. Biochem. Biophys. 2007; 461: 104-112Crossref PubMed Scopus (24) Google Scholar HETEs69Ward N.C. Tsai I.J. Barden A. van Bockxmeer F.M. Puddey I.B. Hodgson J.M. Croft K.D. Hypertension. 2008; 51: 1393-1398Crossref PubMed Scopus (130) Google Scholar Open table in a new tab How might AHR-dependent CYP1-dependent responses be dissected from AHR-dependent CYP1-independent responses (Fig. 1)? One excellent model system is the recently characterized Cyp1a1/1a2/1b1–/– triple-knock-out mouse (6Dragin N. Shi Z. Madan R. Karp C.L. Sartor M.A. Chen C. Gonzalez F.J. Nebert D.W. Mol. Pharmacol. 2008; 73: 1844-1856Crossref PubMed Scopus (57) Google Scholar). The other model system is the Ahr–/– knock-out mouse (reviewed in Refs. 7Frericks M. Meissner M. Esser C. Toxicol. Appl. Pharmacol. 2007; 220: 320-332Crossref PubMed Scopus (100) Google Scholar, 8Hahn M.E. Karchner S.I. Evans B.R. Franks D.G. Merson R.R. Lapseritis J.M. J. Exp. Zool. Part A Comp. Exp. Biol. 2006; 305: 693-706Crossref PubMed Scopus (116) Google Scholar, 9McMillan B.J. Bradfield C.A. Mol. Pharmacol. 2007; 72: 487-498Crossref PubMed Scopus (138) Google Scholar). Whereas Ahr–/– mice have no functional AHR, and therefore, all downstream genes regulated by the AHR should be affected, Cyp1a1/1a2/1b1–/– mice have a functional AHR but lack all three CYP1 enzymes. Therefore, using these two mouse lines, one should now be able to distinguish (in the intact mouse) between all AHR-dependent functions versus the subset of AHR-regulated CYP1-dependent functions. Phenotype of the Cyp1a1/1a2/1b1–/– Mouse—When compared with wild-type mice (with incomplete penetrance), the Cyp1 triple-knock-out F1 mouse exhibited (i) infertility and embryo lethality, (ii) a significantly increased risk of certain birth defects (hydrocephalus, hermaphroditism, and cystic ovaries), and (iii) at least 89 genes significantly up-regulated versus 62 genes down-regulated (6Dragin N. Shi Z. Madan R. Karp C.L. Sartor M.A. Chen C. Gonzalez F.J. Nebert D.W. Mol. Pharmacol. 2008; 73: 1844-1856Crossref PubMed Scopus (57) Google Scholar). All of these phenotypes probably reflect deficiencies in cell proliferation and migration, ion transport, angiogenesis, and/or vascular pO2 sensing, again most likely eicosanoid-related processes (supplemental Table S2). Please see supplemental material (Box 2). Dysregulation of the Inflammatory Response—Finally, an exaggerated response to zymosan-induced peritonitis, along with significant down-regulation of hepatic expression of the Socs2 (suppression of cytokine signaling-2) gene, was seen in Cyp1a1/1a2/1b1–/– mice (6Dragin N. Shi Z. Madan R. Karp C.L. Sartor M.A. Chen C. Gonzalez F.J. Nebert D.W. Mol. Pharmacol. 2008; 73: 1844-1856Crossref PubMed Scopus (57) Google Scholar). Both endogenous and exogenous AHR ligands are known to up-regulate SOCS2 expression. 2,3,7,8-Tetrachlorodibenzo-p-dioxin has been shown to up-regulate SOCS2 expression in lymphocytes in an AHR-dependent fashion (10Boverhof D.R. Tam E. Harney A.S. Crawford R.B. Kaminski N.E. Zacharewski T.R. Mol. Pharmacol. 2004; 66: 1662-1670Crossref PubMed Scopus (50) Google Scholar). Inhibition of dendritic cell production of pro-inflammatory cytokines by the pro-resolution lipoxin eicosanoids is dependent on AHR-driven up-regulation of SOCS2 expression (11Cowart L.A. Wei S. Hsu M.H. Johnson E.F. Krishna M.U. Falck J.R. Capdevila J.H. J. Biol. Chem. 2002; 277: 35105-35112Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). Activation of AHR by both native and aspirin-induced lipoxins triggers SOCS expression; this then leads to ubiquitinylation and proteasomal degradation of TRAF (tumor necrosis factor-α receptor-associated factor)-6 and TRAF-2, key adaptor molecules that couple interleukin-1/Toll-like and tumor necrosis factor receptor family members to intracellular signaling cascades (12Machado F.S. Esper L. Dias A. Madan R. Gu Y. Hildeman D. Serhan C.N. Karp C.L. Aliberti J. J. Exp. Med. 2008; 205: 1077-1086Crossref PubMed Scopus (45) Google Scholar). The decreased SOCS2 expression observed in the triple knock-out is consistent with a potential mechanism for the exaggerated zymosan-induced inflammatory response as well as the possibility that one or more of the AHR-regulated CYP1 enzymes participate in generation of endogenous eicosanoid ligands for AHR. The Ahr–/– knock-out mouse shows a PDV and other AV E. Bradfield C.A. Mol. Pharmacol. 2005; 67: PubMed Scopus (136) Google along with P. T. T. Lee S.S. Kimura S. Nebert D.W. S. J.M. Gonzalez F.J. Science. 1995; 268: PubMed Scopus Google Scholar) and increased to Y. M. H. J. Immunol. 2007; PubMed Scopus Google Scholar). The latter two were in Cyp1a1/1a2/1b1–/– mice (6Dragin N. Shi Z. Madan R. Karp C.L. Sartor M.A. Chen C. Gonzalez F.J. Nebert D.W. Mol. Pharmacol. 2008; 73: 1844-1856Crossref PubMed Scopus (57) Google Scholar). the Cyp1 triple knock-out is also to include PDV and AV these that one or more of the CYP1 enzymes participate in and to an AHR-dependent CYP1-independent is for increased risk of the PDV and AV of endogenous shown to CYP1 and/or AHR include other and Nebert D.W. J. Biol. Chem. Full Text PDF PubMed Google such as and such as and the fatty acid at least different S.D. G.M. M.H. Li V. B. M.S. J. Biochem. Mol. Toxicol. 2001; 15: PubMed Scopus Google Scholar) and lipoxin and the (reviewed in Refs. 9McMillan B.J. Bradfield C.A. Mol. Pharmacol. 2007; 72: 487-498Crossref PubMed Scopus (138) Google Scholar and R. X. 2007; PubMed Scopus Google Scholar). The of such in the intact the in cell and the of for the of these not as as one for AHR ligands. We that is likely to be and specificity and redundancy for endogenous AHR ligands. should now be possible to AHR ligands by from an of of the wild-type mouse with of various of the Cyp1 knock-out that are now Other of of the AHR in cell is seen in the M.P. K.A. Y. J.R. T. L.M. A. A. G.M. J.B. S. A. 2002; PubMed Scopus Google and incredibly of are in the A. Nebert D.W. Biochem. Biophys. Res. 1998; PubMed Scopus Google Scholar). Interestingly, in cells and hepatic in the intact mouse are both with up-regulation of in the of an exogenous S. Nebert D.W. J. Exp. Google Scholar). in the B.J. Bradfield C.A. Mol. Pharmacol. 2007; 72: 487-498Crossref PubMed Scopus (138) Google Scholar, R. X. 2007; PubMed Scopus Google Scholar) and E. C. C. T. T. M. H. P. A. P. H. J. J. S. A. 2007; PubMed Scopus Google as well as of growth in cells, also up-regulate CYP1 and/or AHR (reviewed in 9McMillan B.J. Bradfield C.A. Mol. Pharmacol. 2007; 72: 487-498Crossref PubMed Scopus (138) Google Scholar). to of the to the cell cell and mechanical and and all eicosanoids (supplemental Table S2). in the of knock-out mice in which is by a the is of in and enzyme are in virtually all of this mouse, other the S. Chen C. J. S. Gonzalez F.J. J. Clin. 2007; PubMed Scopus Google Scholar). is with to the S. Chen C. J. S. Gonzalez F.J. J. Clin. 2007; PubMed Scopus Google Scholar). These well with the of AHR, CYP1, and eicosanoids. The of and (and resolution of in the The also eicosanoid of from the AHR function and CYP1 expression in that cell we as a eicosanoids synthesized or by the CYP1 enzymes are released throughout the of the and that these eicosanoids are AHR ligands that then up-regulation in virtually cell the of this eicosanoid synthesis and degradation are not the of the for K.A. Lee J.M. S. K. M. X. E. S. Rev. Ther. 2007; PubMed Scopus (63) Google Scholar, C.M. Breyer M.D. Annu. Rev. 2008; PubMed Scopus Google Scholar, S. V. D.N. D.W. Metab. Drug 2008; PubMed Scopus Google Scholar) and for other eicosanoids S. R. R. R. J. 2007; PubMed Scopus (40) Google Scholar, M. I. A. 2007; Scopus (34) Google Scholar, P. Rev. Med. Chem. 2008; PubMed Scopus Google Scholar) are many of which are but the is in perhaps other also (Fig. about the release of ω-6 and ω-3 fatty acids from and diacylglycerol and about the synthesis and degradation of specific eicosanoids by certain and CYP enzymes well lead to the of new targets. a of eicosanoid and should also in more and possible new in various human specific of We for critical of this and N. for with