Relevance of the aryl hydrocarbon receptor (AhR) for clinical toxicology

Clinical Toxicology

Volumn 47, Issue 7, 2009, Pages 632-642

  Bradshaw, Tracey D ^a   Bell, David R ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

Aryl hydrocarbon receptor; Dioxin; TCDD; Toxicity

Indexed keywords

1,3,8 TRICHLORO 6 METHYLDIBENZOFURAN; 3 INDOLEMETHANOL; 5 FLUORO 2 (4 LYSYLAMINO 3 METHYLPHENYL)BENZOTHIAZOLE; AROMATIC HYDROCARBON RECEPTOR; BENZOTHIAZOLE DERIVATIVE; BILIRUBIN; CARBAZOLE DERIVATIVE; CYCLIC AMP; DIOXIN; FLAVONOID; ICOSANOID; INDIRUBIN; INDOLO (3,2 B) CARBAZOLE AND 3,3' DIINDOLYLMETHANE; PIFITHRIN ALPHA; SULFORAPHANE; TRYPTOPHAN; UNCLASSIFIED DRUG;

ADVERSE OUTCOME; BRAIN DEVELOPMENT; CHEMICAL INTERACTION; CHLORACNE; CLINICAL TRIAL; DIET; HUMAN; NONHUMAN; PROTEIN FUNCTION; REVIEW; SENSITIVITY ANALYSIS; SIGNAL TRANSDUCTION; TOXICOKINETICS; TOXICOLOGY; VASCULARIZATION; ANIMAL; DRUG DEVELOPMENT; DRUG INTERACTION; DRUG POTENTIATION; PHYSIOLOGY;

ANIMALIA;

ANIMALS; DIOXINS; DRUG DISCOVERY; DRUG INTERACTIONS; HUMANS; RECEPTORS, ARYL HYDROCARBON; TOXICOLOGY;

EID: 69149090156     PISSN: 15563650     EISSN: 15569519     Source Type: Journal    
DOI: 10.1080/15563650903140423     Document Type: Review

References (121)

1. Thomas PE, Kouri RE, Hutton JJ. Genetics of aryl hydrocarbon hydroxylase induction in mice - single gene difference between C57BL/6J and DBA/2J. Biochem Genet 1972; 6:157-168.
2. Nebert DW, Goujon FM, Gielen JE. Aryl hydrocarbon hydroxylase induction by polycyclic hydrocarbons - simple autosomal dominant trait in mouse. Nat New Biol 1972; 236:107-110.
3. Thomas PE, Hutton JJ, Taylor BA. Genetic relationship between aryl hydrocarbon hydroxylase inducibility and chemical carcinogen induced skin ulceration in mice. Genetics 1973; 74:655-659.
4. Poland A, Glover E. Genetic expression of arylhydrocarbon hydroxylase by 2,3,7,8-tetrachlorodibenzo-para-dioxin - evidence for a receptor mutation in genetically non-responsive mice. Mol Pharmacol 1975; 11:389-398.
5. Poland A, Glover E, Kende AS. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-para-dioxin by hepatic cytosol - evidence that binding species is receptor for induction of arylhydrocarbon hydroxylase. J Biol Chem 1976; 251:4936-4946.
6. Poland A, Palen D, Glover E. Analysis of the 4 alleles of the murine arylhydrocarbon receptor. Mol Pharmacol 1994; 46:915-921.
7. Poland A, Glover E, Taylor BA. The murine Ah locus - a new allele and mapping to chromosome-12. Mol Pharmacol 1987; 32:471-478.
8. Bradfield CA, Glover E, Poland A. Purification and N-terminal aminoacid- sequence of the Ah receptor from the C57BL/6J mouse. Mol Pharmacol 1991; 39:13-19.
9. Burbach KM, Poland A, Bradfield CA. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci USA 1992; 89:8185-8189.
10. Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Fujii-Kuriyama Y. cDNA cloning and structure of mouse putative Ah receptor. Biochem Biophys Res Commun 1992; 184: 246-253.
11. Ema M, Matsushita N, Sogawa K, Ariyama T, Inazawa J, Nemoto T, Ota M, Oshimura M, Fujii-Kuriyama Y. Human aryl hydrocarbon receptor - functional expression and chromosomal assignment to 7p21. J Biochem 1994; 116:845-851.
12. Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med 2003; 228:111-133.
13. Whitelaw ML, McGuire J, Picard D, Gustafsson JA, Poellinger L. Heatshock protein Hsp90 regulates dioxin receptor function in-vivo. Proc Natl Acad Sci USA 1995; 92:4437-4441.
14. Lin BC, Nguyen LP, Walisser JA, Bradfield CA. A hypomorphic allele of aryl hydrocarbon receptor-associated protein-9 produces a phenocopy of the Ahr-null mouse. Mol Pharmacol 2008; 74:1367-1371.
15. Hollingshead BD, Petrulis JR, Perdew GH. The aryl hydrocarbon (Ah) receptor transcriptional regulator hepatitis B virus X-associated protein 2 antagonizes p23 binding to Ah receptor-Hsp90 complexes and is dispensable for receptor function. J Biol Chem 2004; 279:45652-45661.
16. Fan MQ, Bell AR, Bell DR, Clode S, Fernandes A, Foster PM, Fry JR, Jiang T, Loizou G, MacNicoll A, Miller BG, Rose M, Shaikh-Omar O, Tran L, White S. Recombinant expression of aryl hydrocarbon receptor for quantitative ligand-binding analysis. Anal Biochem 2009; 384:279-287.
17. Pollenz RS. The arylhydrocarbon receptor, but not the arylhydrocarbon receptor nuclear translocator protein, is rapidly depleted in hepatic and nonhepatic culture cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Pharmacol 1996; 49:391-398.
18. Ma Q, Renzelli AJ, Baldwin KT, Antonini JM. Superinduction of CYP1A1 gene expression - regulation of 2,3,7,8-tetrachlorodibenzo-pdioxin- induced degradation of Ah receptor by cycloheximide. J Biol Chem 2000; 275:12676-12683.
19. Peters JM, Narotsky MG, Elizondo G, Fernandez-Salguero PM, Gonzalez FJ, Abbott BD. Amelioration of TCDD-induced teratogenesis in aryl hydrocarbon receptor (AhR)-null mice. Toxicol Sci 1999; 47:86-92.
20. Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ. Arylhydrocarbon receptor-deficient mice are resistant to 2,3,7,8- tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 1996; 140:173-179.
21. Bunger MK, Glover E, Moran SM, Walisser JA, Lahvis GP, Hsu EL, Bradfield CA. Abnormal liver development and resistance to 2,3,7,8- tetrachlorodibenzo-p- dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor. Toxicol Sci 2008; 106:83-92.
22. Nebert DW, Dalton TP, Okey AB, Gonzalez FJ. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 2004; 279:23847-23850.
23. Smart J, Daly AK. Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms. Pharmacogenetics 2000; 10:11-24.
24. Okey AB, Boutros PC, Harper PA. Polymorphisms of human nuclear receptors that control expression of drug-metabolizing enzymes. Pharmacogenet Genomics 2005; 15:371-379.
25. Harper PA, Wong JMY, Lam MSM, Okey AB. Polymorphisms in the human AH receptor. Chem Biol Interact 2002; 141:161-187.
26. Geusau A, Abraham K, Geissler K, Sator MO, Stingl G, Tschachler E. Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and laboratory effects. Environ Health Perspect 2001; 109:865-869.
27. Herxheimer K. Uber chlorakne. Munch Med Wochenschr 1899; 46:278.
28. Drinker CK, Warren MF, Bennett GA. The problem of possible systemic effects from certain chlorinated hydrocarbons. J Ind Hyg Toxicol 1937; 19:283-311.
29. Poland A, Knutson JC. 2,3,7,8-Tetrachlorodibenzo-para-dioxin and related halogenated aromatic-hydrocarbons - examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 1982; 22:517-554.
30. IPCS, ed. Polychlorinated Dbinzo-Para-Dioxins and Dibenzofurans. Vammala, Finland: World Health Organisation; 1988.
31. Yamamoto O, Tokura Y. Photocontact dermatitis and chloracne: two major occupational and environmental skin diseases induced by different actions of halogenated chemicals. J Dermatol Sci 2003; 32:85-94.
32. Oliver RM. Toxic effects of 2,3,7,8-tetrachlorodibenzo 1,4-dioxin in laboratory workers. Br J Ind Med 1975; 32:49-53.
33. Coenraads PJ, Olie K, Tang NJ. Blood lipid concentrations of dioxins and dibenzofurans causing chloracne. Br J Dermatol 1999; 141: 694-697.
34. Scerri L, Zaki I, Millard LG. Severe halogen acne due to a trifluoromethylpyrazole derivative and its resistance to isotretinoin. Br J Dermatol 1995; 132:144-148.
35. MacKenzie AR, Brooks S. Chloracnegen caution. Chem Ind 1998: 902, 912.
36. Pohjanvirta R, Tuomisto J. Han Wistar rats are exceptionally resistant to TCDD. 2. Arch Toxicol 1987; 11:344-347. (Pubitemid 17091603)
37. Poland A, Glover E. Estimate of the maximum in vivo covalent binding of 2,3,7,8-tetrachlorodibenzo-para-dioxin to rat-liver protein, ribosomal- RNA, and DNA. Cancer Res 1979; 39:3341-3344.
38. Bell DR, Clode S, Fan MQ, Fernandes A, Foster PM, Jiang T, Loizou G, MacNicoll A, Miller BG, Rose M, Tran L, White S. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar (Han) rat. I: no decrease in epididymal sperm count after a single acute dose. Toxicol Sci 2007; 99:214-223.
39. Gray LE, Ostby JS, Kelce WR. A dose-response analysis of the reproductive effects of a single gestational dose of 2,3,7,8-tetrachlorodibenzo- p-dioxin in male Long Evans Hooded rat offspring. Toxicol Appl Pharmacol 1997; 146:11-20.
40. Roman BL, Peterson RE. In utero and lactational exposure of the male rat to 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs prostate development - 1. Effects on gene expression. Toxicol Appl Pharmacol 1998; 150:240-253.
41. Bell DR, Clode S, Fan MQ, Fernandes A, Foster PM, Jiang T, Loizou G, MacNicoll A, Miller BG, Rose M, Tran L, White S. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar (Han) rat. II: chronic dosing causes developmental delay. Toxicol Sci 2007; 99:224-233.
42. Jiang T, Bell DR, Clode S, Fan MQ, Fernandes A, Foster PM, Loizou G, MacNicoll A, Miller BG, Rose M, Tran L, White S. A truncation in the aryl hydrocarbon receptor of the CRL: WI(Han) rat does not affect the developmental toxicity of TCDD. Toxicol Sci 2009; 107:512-521.
43. Huuskonen H, Unkila M, Pohjanvirta R, Tuomisto J. Developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the most TCDD-resistant and TCDD-susceptible rat strains. Toxicol Appl Pharmacol 1994; 124:174-180.
44. Fries GF, Marrow GS. Retention and excretion of 2,3,7,8- tetrachlorodibenzo- para-dioxin by rats. J Agric Food Chem 1975; 23:265-269.
45. Rose JQ, Ramsey JC, Wentzler TH, Hummel RA, Gehring PJ. Fate of 2,3,7,8-tetrachlorodibenzo-para-dioxin following single and repeated oral doses to rat. Toxicol Appl Pharmacol 1976; 36:209-226.
46. Weber LWD, Ernst SW, Stahl BU, Rozman K. Tissue distribution and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats after intravenous injection. Fundam Appl Toxicol 1993; 21:523-534.
47. Bell DR, Clode S, Fan MQ, Fernandes A, Foster PM, Jiang T, Loizou G, MacNicoll A, Miller BG, Rose M, Tran L, White S. Relationships between tissue levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mRNAs, and toxicity in the developing male Wistar(Han) rat. Toxicol Sci 2007; 99:591-604. (Pubitemid 351753073)
48. Poland A, Teitelbaum P, Glover E. [I-125]2-iodo-3,7,8-trichlorodibenzo- p-dioxin-binding species in mouse-liver induced by agonists for the Ah receptor - characterization and identification. Mol Pharmacol 1989; 36:113-120.
49. Geyer HJ, Schramm KW, Feicht EA, Behechti A, Steinberg C, Brüggemann R, Poiger H, Henkelmann B, Kettrup A. Half-lives of tetra-, penta-, hexa-, hepta-, and octachlorodibenzo-p-dioxin in rats, monkeys, and humans - a critical review. Chemosphere 2002; 48:631-644.
50. Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. Concentration- dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. J Expo Anal Environ Epidemiol 2005; 15:51-65.
51. Kreuzer PE, Csanady GA, Baur C, Kessler W, Päpke O, Greim H, Filser JG. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch Toxicol 1997; 71:383-400.
52. Kerger BD, Leung HW, Scott P, Paustenbach DJ, Needham LL, Patterson DG Jr, Gerthoux PM, Mocarelli P. Age- and concentrationdependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children. Environ Health Perspect 2006; 114:1596-1602.
53. Leung HW, Kerger BD, Paustenbach DJ. Elimination half-lives of selected polychlorinated dibenzodioxins and dibenzofurans in breastfed human infants. J Toxicol Environ Health A 2006; 69:437-443.
54. Poland A, Glover E. Comparison of 2,3,7,8-tetrachlorodibenzo-paradioxin, a potent inducer of arylhydrocarbon hydroxylase, with 3-methylcholanthrene. Mol Pharmacol 1974; 10:349-359.
55. Powell-Coffman JA, Bradfield CA, Wood WB. Caenorhabditis elegans orthologs of the aryl hydrocarbon receptor and its heterodimerization partner the aryl hydrocarbon receptor nuclear translocator. Proc Natl Acad Sci USA 1998; 95:2844-2849.
56. Bell DR, Poland A. Binding of aryl hydrocarbon receptor (AhR) to AhR-interacting protein - the role of hsp90. J Biol Chem 2000; 275:36407-36414.
57. Qin HT, Powell-Coffman JA. The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development. Dev Biol 2004; 270:64-75.
58. Huang X, Powell-Coffman JA, Jin YS. The AHR-1 aryl hydrocarbon receptor and its co-factor the AHA-1 aryl hydrocarbon receptor nuclear translocator specify GABAergic neuron cell fate in C-elegans. Development 2004; 131:819-828.
59. Qin HT, Zhai ZW, Powell-Coffman JA. The Caenorhabditis elegans AHR-1 transcription complex controls expression of soluble guanylate cyclase genes in the URX neurons and regulates aggregation behavior. Dev Biol 2006; 298:606-615.
60. Campbell SJ, Henderson CJ, Anthony DC, Davidson D, Clark AJ, Wolf CR. The murine Cyp1a1 gene is expressed in a restricted spatial and temporal pattern during embryonic development. J Biol Chem 2005; 280:5828-5835.
61. Dragin N, Shi ZQ, Madan R, Karp CL, Sartor MA, Chen C, Gonzalez FJ, Nebert DW. Phenotype of the Cyp1a1/1a2/1b1(-/-) triple-knockout mouse. Mol Pharmacol 2007; 73:1844-1856.
62. Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ. Immunesystem impairment and hepatic-fibrosis in mice lacking the dioxinbinding Ah receptor. Science 1995; 268:722-726.
63. Schmidt JV, Su GHT, Reddy JK, Simon MC, Bradfield CA. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci USA 1996; 93:6731-6736.
64. Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M, Fujii-Kuriyama Y. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells 1997; 2:645-654.
65. Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J, Fujii-Kuriyama Y, Ishikawa T. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 2000; 97:779-782.
66. Lahvis GP, Lindell SL, Thomas RS, McCuskey RS, Murphy C, Glover E, Bentz M, Southard J, Bradfield CA. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc Natl Acad Sci USA 2000; 97:10442-10447.
67. Lahvis GP, Pyzalski RW, Glover E, Pitot HC, McElwee MK, Bradfield CA. The aryl hydrocarbon receptor is required for developmental closure of the ductus venosus in the neonatal mouse. Mol Pharmacol 2005; 67:714-720.
68. Walisser JA, Glover E, Pande K, Liss AL, Bradfield CA. Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc Natl Acad Sci USA 2005; 102:17858-17863.
69. Walisser JA, Bunger MK, Glover E, Bradfield CA. Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development. Proc Natl Acad Sci USA 2004; 101:16677-16682.
70. Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci USA 2008; 105:9721-9726.
71. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL. Control of T-reg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 453:65-71.
72. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B. The aryl hydrocarbon receptor links T(H)17-cell-mediated autoimmunity to environmental toxins. Nature 2008; 453:106-109.
73. Esser C. The immune phenotype of AhR null mouse mutants: not a simple mirror of xenobiotic receptor over-activation. Biochem Pharmacol 2009; 77:597-607.
74. Graham MJ, Lake BG. Induction of Drug Metabolism: Species Differences and Toxicological Relevance. Guildford, England: Elsevier Ireland Ltd; 2008:184-191.
75. Lu C, Li AP. Species comparison in P450 induction: effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog. Chem Biol Interact 2001; 134:271-281.
76. Fang AF, Damle BD, LaBadie RR, Crownover PH, Hewlett D, Glue PW. Significant decrease in nelfinavir systemic exposure after omeprazole coadministration in healthy subjects. Pharmacotherapy 2008; 28:42-50.
77. Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors - what the practising physician needs to know. Drugs 2003; 63:2739-2754.
78. Furuta S, Kamada E, Suzuki T, Sugimoto T, Kawabata Y, Shinozaki Y, Sano H. Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine and omeprazole. Xenobiotica 2001; 31:1-10. (Pubitemid 32337057)
79. Hu WY, Sorrentino C, Denison MS, Kolaja K, Fielden MR. Induction of Cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol 2007; 71:1475-1486.
80. Shiizaki K, Ohsako S, Kawanishi M, Yagi T. Omeprazole alleviates benzo[a]pyrene cytotoxicity by inhibition of CYP1A1 activity in human and mouse hepatoma cells. Basic Clin Pharmacol Toxicol 2008; 103:468-475.
81. Quattrochi LC, Tukey RH. Nuclear uptake of the Ah (Dioxin) receptor in response to omeprazole - transcriptional activation of the human Cyp1a1 gene. Mol Pharmacol 1993; 43:504-508.
82. Lemaire G, Delescluse C, Pralavorio M, Ledirac N, Lesca P, Rahmani R. The role of protein tyrosine kinases in CYP1A1 induction by omeprazole and thiabendazole in rat hepatocytes. Life Sci 2004; 74: 2265-2278.
83. Yoshinari K, Ueda R, Kusano K, Yoshimura T, Nagata K, Yamazoe Y. Omeprazole transactivates human CYP1A1 and CYP1A2 expression through the common regulatory region containing multiple xenobioticresponsive elements. Biochem Pharmacol 2008; 76:139-145.
84. Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 2003; 43:309-334.
85. Hoagland MS, Hoagland EM, Swanson HI. The p53 inhibitor pifithrinalpha is a potent agonist of the aryl hydrocarbon receptor. J Pharmacol Exp Ther 2005; 314:603-610.
86. Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Wade CE, Dittenber DA, Kalnins RP, Frauson LE, Park CN, Barnard SD, Hummel RA, Humiston CG. Results of a 2-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo- para-dioxin in rats. Toxicol Appl Pharmacol 1978; 46:279-303.
87. Gierthy JF, Bennett JA, Bradley LM, Cutler DS. Correlation of in-vitro and in-vivo growth suppression of Mcf-7 human breast-cancer by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Res 1993; 53:3149-3153.
88. Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC. The seveso studies on early and long-term effects of dioxin exposure: a review. Environ Health Perspect 1998; 106:625-633.
89. Bertazzi PA, Pesatori AC, Consonni D, Tironi A, Landi MT, Zocchetti C. Cancer incidence in a population accidentally exposed to 2,3,7,8- tetrachlorodibenzo- para-dioxin. Epidemiology 1993; 4:398-406.
90. McDougal A, Gupta MS, Morrow D, Ramamoorthy K, Lee JE, Safe SH. Methyl-substituted diindolylmethanes as inhibitors of estrogeninduced growth of T47D cells and mammary tumors in rats. Breast Cancer Res Treat 2001; 66:147-157.
91. Pearce ST, Liu H, Radhakrishnan I, Abdelrahim M, Safe S, Jordan VC. Interaction of the aryl hydrocarbon receptor ligand 6-methyl-1,3,8- trichlorodibenzofuran with estrogen receptor alpha. Cancer Res 2004; 64:2889-2897.
92. Safe S, Wormke M, Walker K, Dickerson R, Castro-Rivera E. Estrogen receptor signaling and crosstalk with the Ah receptor in endometrial cancer cells. In: Kuramoto H, Nishida M, eds. Cell and Molecular Biology Biology of Endometrial Carcinoma. Tokyo, Japan: Springer-Verlag Tokyo; 2002:109-122.
93. Ftitz WA, Lin TM, Safe S, Moore RW, Peterson RE. The selective aryl hydrocarbon receptor modulator 6-methyl-1,3,8-trichlorodibenzofuran inhibits prostate tumor metastasis in TRAMP mice. Biochem Pharmacol 2009; 77:1151-1160.
94. Bradshaw TD, Westwell AD. The development of the antitumour benzothiazole prodrug, Phortress, as a clinical candidate. Curr Med Chem 2004; 11:1009-1021.
95. Chua MS, Kashiyama E, Bradshaw TD, Stinson SF, Brantley E, Sausville EA, Stevens MF. Role of CYP1A1 in modulation of antitumor properties of the novel agent 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) in human breast cancer cells. Cancer Res 2000; 60:5196-5203.
96. Loaiza-Perez AI, Trapani V, Hose C, Singh SS, Trepel JB, Stevens MF, Bradshaw TD, Sausville EA. Aryl hydrocarbon receptor mediates sensitivity of MCF-7 breast cancer cells to antitumor agent 2-(4-amino-3- methylphenyl) benzothiazole. Mol Pharmacol 2002; 61:13-19.
97. Leong CO, Gaskell M, Martin EA, Heydon RT, Farmer PB, Bibby MC, Cooper PA, Double JA, Bradshaw TD, Stevens MF. Antitumour 2-(4-aminophenyl) benzothiazoles generate DNA adducts in sensitive tumour cells in vitro and in vivo. Br J Cancer 2003; 88:470-477.
98. Hutchinson I, Chua MS, Browne HL, Trapani V, Bradshaw TD, Westwell AD, Stevens MF. Antitumor benzothiazoles. 14. Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl) benzothiazoles. J Med Chem 2001; 44:1446-1455.
99. Bradshaw TD, Bibby MC, Double JA, Fichtner I, Cooper PA, Alley MC, Donohue S, Stinson SF, Tomaszewjski JE, Sausville EA, Stevens MF. Preclinical evaluation of amino acid prodrugs of novel antitumor 2-(4-amino-3-methylphenyl) benzothiazoles. Mol Cancer Ther 2002; 1:239-246.
100. Bazzi R, Bradshaw TD, Rowlands JC, Stevens MFG, Bell DR. 2-(4- Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the aryl hydrocarbon receptor. Toxicol Appl Pharmacol 2009; 237:102-110.
101. Loaiza-Perez AI, Kenney S, Boswell J, Hollingshead M, Alley MC, Hose C, Ciolino HP, Yeh GC, Trepel JB, Vistica DT, Sausville EA. Aryl hydrocarbon receptor activation of an antitumor aminoflavone: basis of selective toxicity for MCF-7 breast tumor cells. Mol Cancer Ther 2004; 3:715-725.
102. Meng LH, Shankavaram U, Chen C, Agama K, Fu HQ, Gonzalez FJ, Weinstein J, Pommier Y. Activation of aminoflavone (NSC 686288) by a sulfotransferase is required for the antiproliferative effect of the drug and for induction of histone gamma-H2AX. Cancer Res 2006; 66:9656-9664.
103. McLean L, Soto U, Agama K, Francis J, Jimenez R, Pommier Y, Sowers L, Brantley E. Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells. Internat J Cancer 2006; 122:1665-1674.
104. Denison MS, Han DH, Nagy SR, Zhao B, Baston DS, Hayashi A, Knockaert M, Meijer L. Indirubins as activators of the aryl hydrocarbon receptor signal transduction pathway. In: Meijer L, Guyard N, Skaltsounis L, Eisenbrand G, eds. Indirubin, the Red Shade of Indigo. Les Eyzies de Tayac, France: Life in Progress Editions; 2003:157-167.
105. Yu JL, Nestrick TJ, Allen R, Savage PE. Microcontaminants in pentachlorophenol synthesis. 1. New bioassay for microcontaminant quantification. Ind Eng Chem Res 2006; 45:5199-5204.
106. Sanderson JT, Slobbe L, Lansbergen GWA, Safe S, van den Berg M. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and diindolylmethanes differentially induce cytochrome P450 1A1, 1B1, and 19 in H295R human adrenocortical carcinoma cells. Toxicol Sci 2001; 61:40-48.
107. Ohtake F, Fujii-Kuriyama Y, Kato S. AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions. Biochem Pharmacol 2009; 77:474-484.
108. Okino ST, Pookot D, Basak S, Dahiya R. Toxic and chemopreventive ligands preferentially activate distinct aryl hydrocarbon receptor path- ways: implications for cancer prevention. Cancer Prev Res 2009; 2:251-256.
109. Medjakovic S, Jungbauer A. Red clover isoflavones biochanin a and formononetin are potent ligands of the human aryl hydrocarbon receptor. J Steroid Biochem Mol Biol 2008; 108:171-177.
110. Moon YJ, Wang XD, Morris ME. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro 2006; 20:187-210.
111. Anwar-Mohamed A, El-Kadi AOS. Sulforaphane induces CYP1A1 mRNA, protein, and catalytic activity levels via an AhR-dependent pathway in murine hepatoma Hepa 1c1c7 and human HepG2 cells. Cancer Lett 2009; 275:93-101.
112. Gielen JE, Nebert DW. Aryl hydrocarbon hydroxylase induction in mammalian liver cell culture.1. Stimulation of enzyme activity in nonhepatic cells and in hepatic cells by phenobarbital, polycyclic hydrocarbons, and 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane. J Biol Chem 1971; 246:5189-5198.
113. Jinno A, Maruyama Y, Ishizuka M, Kazusaka A, Nakamura A, Fujita S. Induction of cytochrome P450-1A by the equine estrogen equilenin, a new endogenous aryl hydrocarbon receptor ligand. J Steroid Biochem Mol Biol 2006; 98:48-55.
114. Seidel SD, Winters GM, Rogers WJ, Ziccardi MH, Li V, Keser B, Denison MS. Activation of the Ah receptor signaling pathway by prostaglandins. J Biochem Mol Toxicol 2001; 15:187-196.
115. Nebert DW, Karp CL. Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)- metabolized eicosanoids and AHR Biology. J Biol Chem 2008; 283:36061-36065.
116. Zatloukalova J, Svihalkova-Sindlerova L, Kozubik A, Krcmar P, Machala M, Vondracek J. Beta-naphthoflavone and 3-methoxy-4- nitroflavone exert ambiguous effects on Ah receptor-dependent cell proliferation and gene expression in rat liver "stem-like" cells. Biochem Pharmacol 2007; 73:1622-1634.
117. Marko D, Schatzle S, Friedel A, Genzlinger A, Zankl H, Meijer L, Eisenbrand G. Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer 2001; 84:283-289.
118. Baroukiabi R, Coumoul X, Fernandez-Salgueroc PM. The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett 2007; 581:3608-3615.
119. Bittinger MA, Nguyen LP, Bradfield CA. Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor. Mol Pharmacol 2003; 64:550-556.
120. Wincent E, Amini N, Luecke S, Glatt H, Bergman J, Crescenzi C, Rannug A, Rannug U. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[ 3,2-b]carbazole is present in humans. J Biol Chem 2009; 284:2690-2696.
121. Rannug A, Fritsche E. The aryl hydrocarbon receptor and light. Biol Chem 2006; 387:1149-1157.