Aromatic hydrocarbon receptor

The biological properties of dioxin include an ability to bind to a protein known as the AH (aromatic hydrocarbon) receptor Dioxin IS not a hydrocarbon but it shares a certain structural property with aromatic hydrocarbons Try constructing molecular models of dioxin and anthracene to see these similarities... 

The biological properties of dioxin include an ability to bind to a protein known as the AH (aromatic hydrocarbon) receptor. 

Puga, A., et. al., Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest, J. Biol. Chem., 275, 2943, 2000. 

Lavin, A., Hahn, D., and Gasiewicz, T. A., Expression of functional aromatic hydrocarbon receptor and aromatic hydrocarbon nuclear translocator proteins in murine bone marrow stromal cells, Arch. Biochem. Biophys., 352, 9, 1998. 

Cikryt P, Josephy PD. 1989. Binding of chlorinated benzidines to the rat hepatic aromatic hydrocarbon receptor. Chem Biol Interactions 72(l,2) 57-64. 

Antiproliferative compounds are easily detected using cell line or colonyforming unit (CPU) assays. Some of the potential mechanisms of non-antipro-liferative compounds leading to bone marrow toxicity include mitochondrial dysfunction [5, 6], aromatic hydrocarbon receptor (AhR) activation, receptor-mediated, altered receptor expression [7] and reactive intermediates [8, 9], but this list may grow with additional research as the mechanism(s) leading to bone marrow toxicity is still unknown for many compounds and will require significant amount of effort to elucidate. The next paragraphs briefly describe these potential mechanisms. 

T. A. Gasiewicz. Influence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensate. Carcinogenesis 1998 19(11) 2037-2042. 

Perhaps the best understood example of induction involves induction of the aromatic hydrocarbon receptor (AhR) by compounds such as TCDD and 3-methylcholanthrene. The use of suitable inhibitors of RNA and DNA polymerase activity has shown that inhibitors of RNA synthesis such as actinomycin D and mercapto(pyridethyl)benzimida-zole block aryl hydrocarbon hydroxylase induction, whereas hydroxyurea, at levels that completely block the incorporation of thymidine into DNA, has no effect. Thus it appears that the inductive effect is at the level of transcription and that DNA synthesis is not required. 

Ko HP, Okino ST, Ma Q, etal. 1996. Dioxin-induced CYP1A1 transcription in vivo The aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure. Mol Cell Biol 16 430-436. 

Abbreviations. AhR, aromatic hydrocarbon receptor TCDD, tetrachlorodibenzodioxin PXR, pregnenolone-16a-nitrile-X-receptor PCN, pregnenolone-16a-nitrile CAR, constitutive androstane receptor MC, methylcholanthrene PPARa, peroxisome proliferated-activated receptor-a FXR, famesoid-X-receptor LXR, liver-X-receptor RXR, retinod-X-receptor 5-HETE, 5-OH-eicosatetraenoic acid LTB4, leukotriene B4 13-HODE, hydroxyoctadecadienoic acid DMXAA, dimethylxan-thenone-4-acetic acid. 

Matikainen T, Perez Gl, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, Laine J, Sakai T, Korsmeyer SJ, Casper RF, Sherr DH, Tilly JL (2001) Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet, 28 355-360. 

Matikainen TM, Moriyama T, Morita Y, Perez Gl, Korsmeyer SJ, Sherr DH, Tilly JL (2002) Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology, 143 615-620. 

TCDD (Dioxin) toxicity and the aromatic hydrocarbon receptor. . . 1543... 

Nebert, D.W., Roe, A.L., Dieter, M.Z., Solis, W.A., Yang, Y., Dalton, T.P. (2000). Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem. Pharmacol. 59 65-85. 

Chang C-Y, Puga A. 1998. Constitutive activation of the aromatic hydrocarbon receptor. Molec. Cell. Biol. 18 525-35... 

Ma Q, Whitlock JP Jr. 1996. The aromatic hydrocarbon receptor modulates the Hepa lclc7 cell cycle and differentiated state independently of dioxin. Molec. Cell. Biol. 16 2144-50... 

Boyd GW, Coombs MM, Ioannides C. 1995. CYP1 induction, binding to the hepatic aromatic hydrocarbon receptor and mutagenicity of a series of 11-alkoxy cyclopenta[a]phenanthren-17-ones a structure activity relationship. Toxicology 95 27-35... 

Roy, N.K. and I. Wirgin. Characterization of the aromatic hydrocarbon receptor gene and its expression in Atlantic tomcod. Arch. Biochem. Biophys. 344 373—386, 1997. 

Okino, S.T. and J.P. Whitlock. The aromatic hydrocarbon receptor, transcription, and endocrine aspects of dioxin action. Vitam. Horn. 59 241-264, 2000. 

Safa, B., C. Lee, and D.S. Riddick (1997). Role of the aromatic hydrocarbon receptor in the suppression of cytochrome P-450 2C11 by polycyclic aromatic hydrocarbons. Toxicol. Lett. 90, 163-175. 

Anttila, S., P Tuominen, A. Hirvonen, M. Nurminen, A. Kaijalainen, O. Hankinsonera/. (2001). CYPIAI levels in lung tissue of tobacco smokers and polymorphisms of CYPIAI and aromatic hydrocarbon receptor. Pharmacogenetics 11, 501-509. 

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