Aryl hydrocarbon hydroxylase receptors

Dermal treatment of healthy volunteers with 10% coal tar for 4 days produced an 18-fold induction of CYP1A1 mRNA levels in coal-tar-treated skin (Li et al. 1995). In vitro incubation of DNA with coal tar fume concentrates in the presence of mouse and yeast microsomes expressing various cytochrome P450 isoforms or the aryl hydrocarbon hydroxylase receptor (AHR) demonstrated that coal tar fume condensates require metabolic activation to produce DNA adducts (Genevois et al. 1998). Both the AHR and CYP1A were involved in the metabolism of coal tar fume condensate. It was also shown that the reactive metabolites formed by CYP1A are substrates for microsomal epoxide hydrolase. 

Laboratory studies have reported an excellent correlation between the toxicities of the dibenzo-p-dioxins and related compounds and their abilities to induce aryl hydrocarbon hydroxylase (AHH) activity (Poland and Knutson 1982), suggesting that some mechanistic features may be common to both the toxic and AHH-inducing activities of these compounds. Indeed, both the toxicities and the AHH-inducing activities of the dibenzo-p-diox-ins have found to correlate well with binding affinities to a cytosolic receptor (Poland, Greenlee, and Kende 1979 Poland and Knutson 1982). 

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. 

Denomme MA, Homonoko K, Fujita T, et al. 1985. Effects of substituents on the cytosolic receptor-binding affinities of aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. Mol Pharmacol 27 656-661. 

Harris M, Piskorska-Pliszczynska J, Zacharewski T, et al. 1989a. Structure-dependent induction of aryl hydrocarbon hydroxylase in human breast cancer cell lines and characterization of the Ah receptor. 

Poland A, Glover E, Kende AS. 1976. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol Evidence that the binding species is a receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem 251 4936-4946. 

Roberts EA, Johnson KC, Harper PA, et al. 1990. Characterization of the Ah receptor mediating aryl hydrocarbon hydroxylase induction in the human liver cell line HepG2. Arch Biochem Biophys... 

Poland, A. Kende, A. The genetic expression of aryl hydrocarbon hydroxylase activity Evidence for a receptor mutation in nonresponsive mice. In Origins of Human Cancer. Cold Spring Harbor Symposium, New York, 1977 847-967... 

Metabolites of PCBs also exert biological effects. The Ah-receptor mediated responses, however, are probably caused by the parent compounds only. The effects of hydroxylated PCBs include inhibition of cytochrome P450-dependent enzyme activities and competitive interference with thyroid hormone and vitamin A metabolism.89,90 Methylsulfonyl-PCBs have been shown to inhibit aryl hydrocarbon hydroxylase activity91 and to elicit phenobarbital-type toxicity and may in fact be responsible for the observed effect presumed to be caused by the parent compound.92... 

Many of the toxic and biological effects induced by polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and PCBs such as carcinogenesis, reproductive disturbances and immunotoxic effects are believed to be mediated via the hepatic cytosolic aryl hydrocarbon receptor (Ah receptor) [254,255]. Based on in vitro and in vivo studies, the toxicity of individual organochlorines have been determined relative to 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD) and expressed as toxic equivalency factors (TEFs) [254, 256]. In addition to PCDD/F, structurally related PCBs and PCNs bind to the Ah receptor. After binding to the Ah-receptor, the receptor-ligand complex is transferred into the nucleus where it binds to specific DNA sequences and causes transcription of structural genes, which in turn causes synthesis of various cytochrome P4501A1-dependent enzymes such as ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH). TEFs for PCNs have been estimated from enzyme-induction assays of EROD and AHH [10, 257] and Luciferase assays in rat cells [12] cf. Table 4. 

Dibenzofuran induces hepatic, skin, and lung cytochrome P450 lAl, 1A2, and aryl hydrocarbon hydroxylase in rats. Thus, toxicity results from aryl hydrocarbon receptor signal transduction pathway. Bioactivation of many polycyclic hydrocarbon carcinogens is mediated by these enzymes. 

Kafafi SA, Afeefy HY, Said HK, Kafafi AG. 1993. Relationship between aryl hydrocarbon receptor binding, induction of aryl hydrocarbon hydroxylase and 7-ethyoxyresorufin o-deethylase enzymes and toxic activities of aromatic xenobi-otics in animals. A new model. Chem. Res. Toxicol. 6 328-34... 

Tetrachlorodibenzo-j -dioxin (2.28a), the much-discussed contaminant of trichlorophenol, is taken up by a receptor protein in the cytosol of liver, then transported to the nucleus where it induces cytochrome P-450 and aryl hydrocarbon hydroxylase. These seem to be beneficial properties, but in some strains of mice it induces expression of other genes which effects cellular involution, division, and differentiation, presumably using a normal cell-... 

Various conceptual DFT-based reactivity indices in association with some new parameters are successfully employed in the development of stronger QSAR/QSTR models [332]. Deeper correlations of the toxicity of different classes of organic compounds like chlorinated benzenes [333], polychlorinated biphenyls [312, 334—336], and benzidine [337] at DFT level of theory are reported. The toxicity of the polychlorinated biphenyls as well as benzidine is itrfluenced by its electron affinity and planarity. The interactions of the chlorinated benzo-derivatives and benzidine with other biomolecules like nucleic acid/base pairs or aryl hydrocarbon hydroxylase (AHH) receptors are primarily of charge-transfer type, which can be quantitatively assessed from Parr to Pearson formula [254] and can be given as... 

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