The Ah Receptor: Controlling Factor in the Induction of Drug-Metabolizing Enzymes by Certain Chemical Carcinogens and Other Environmental Pollutants

Eisen, Howard J.; Hannah, Rita R.; Legraverend, Catherine; Okey, Allan B.; Nebert, Daniel W.

doi:10.1016/b978-0-12-452810-9.50012-7

Cited by 52 publications

(40 citation statements)

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“…Cysteine 456 is in a more hydrophobic environment than cysteine 158. Because P3-450 metabolizes very hydrophobic drugs and polycyclic hydrocarbon carcinogens (4,19), it is reasonable to presume that its enzyme active-site is in a hydrophobic domain. These data, especially when coupled with the homology data in Fig.…”

Section: Comparison With Other P-450 Protein Sequencesmentioning

confidence: 99%

“…Phenobarbital-induced mouse liver mRNA does not hybridize on Northern blots (13) or by Rot analysis (14) to mouse P1-450 cDNA, nor does 3-methylcholanthrene-induced rat liver mRNA hybridize measurably to rat P-450b (15,16), rat P-450e (17), or mouse P-450b (18) cDNA clones. The 3-methylcholanthrene-inducible P-450 gene family is regulated by the cytosolic Ah receptor (19). The receptor is known to bind avidly (Kd -1 n1M) to such polycyclic aromatic inducers as 3-methylcholanthrene, 2,3,7,8-tetrachlorodibenzo-p-dioxi.…”

Section: Introductionmentioning

confidence: 99%

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Mouse cytochrome P₃-450: complete cDNA and amino acid sequence

1984

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A full-length cDNA clone (1,894 homology, and nucleotides 1068 to 1260, 69Z homology, with portions of rat P-450b exons 2 and 7, respectively. P3-450 shows 62% homology in the socalled "highly conserved region" of 39 nucleotides in the rat P-450b and P-450e and the mouse P-450b. These results indicate that P3-450, P-450b and P-450e arose from a common ancestral gene. Cysteinyl peptide-coding regions were examined: P3-450 nucleotides 1405 to 1464 exhibit 61% homology, and nucleotides 502 to 552 exhibit 37% homology, when compared with their corresponding regions in the rat P-450b gene. These data support the likelihood that cysteine 456 is the thiolate ligand to the heme iron in the P3-450 enzyme active-site. INTRODUCTIONA large portion of drug-metabolizing enzyme activity arises from the membrane-bound multicomponent cytochrome P-450 system (1, 2). Endogenous substrates of P-450 include steroids, fatty acids, biogenic amines, prostaglandins and leukotrienes. Foreign substrates include almost all drugs, chemical carcinogens, and other environmental pollutants numbering in the tens of thousands; hence, the recommended nomenclature for P-450-mediated catalytic activity is "multisubstrate monooxygenase" (3).

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Section: Comparison With Other P-450 Protein Sequencesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mouse cytochrome P₃-450: complete cDNA and amino acid sequence

1984

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“…The role of AHH in the metabolism of PAH is well established (4,(25)(26)(27)(28)(29)(30)(31). Thus its role in the ultimate action of the reactive derivative in the process of carcinogenesis may be defined.…”

Section: Discussionmentioning

confidence: 99%

“…Ectopic hormone and inappropriate gene expression are commonly found to be associated with neoplastic transformation of cells. BaP and several other members of the PAHs have been found to induce aryl hydrocarbon hydroxylase (AHH) in different mammalian cell systems (4). These inducers of AHH also enhance the expression of alpha-fetoprotein gene (5); activities of phospholipase A2 (6); cytosolic aldehyde dehydrogenase (7); membranebound gamma-glutamyl transpeptidase (8); choline kinase (9); and ethanolamine kinase (9).…”

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Mechanism of benzo(a)pyrene induction of alpha-human chorionic gonadotropin gene expression in human lung tumor cells

1986

Lung Cancer

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Human lung cells (ChaGo) derived from a bronchogenic carcinoma synthesize and secrete in the culture medium the alpha subunit of the glycoprotein hormone, human chorionic gonadotropin (alpha-hCG). The synthesis of alpha-hCG by ChaGo cells could be further stimulated by treatment with sublethal concentrations of the polycyclic aromatic hydrocarbons (PAHs), benzo(a)pyrene (gaP), or dimethylbenzanthracene. The production of alpha-hCG could be correlated to the levels of alpha-hCG-specific mRNA sequences in control and PAH-treated cells. Further analysis of the RNA species (Northern blot) revealed that the level of the mature (~1.0 kb) and the high molecular weight alpha-hCG specific nuclear RNA sequences (~2.2 and 5 kb) were all greater in PAH-treated cells.Addition of [3H]BaP (0.25 #g/ml) in the culture medium of ChaGo cells led to immediate uptake of the radioactive compound apparently by simple diffusion. SDS PAGE and subsequent fluorography revealed that the radioactive compound interacted and formed covalent complexes with cytoplasmic and nuclear proteins. This covalent interaction of the [3H]BaP molecule with cellular proteins could be significantly inhibited by either inhibiting the activity of the enzyme aryl hydrocarbon hydroxylase with 7,8-benzoflavone or by reducing the cellular concentration of the enzyme by simultaneous incubation with cycloheximide. These results suggested that in ChaGo cells, the observed covalent complexes were formed by the interaction of the BaP metabolites with cellular proteins. The concentrations at which 7,8-benzoflavone or cycloheximide inhibited (a) formation of metabolites from [3H]BaP and (b) their covalent interaction with cell protein did not affect the BaP-induced stimulation of alphahCG gene expression. However, the cytotoxic effects of BaP in ChaGo cells seemed to be exerted by the metabolism of the compounds. Results presented in this report suggest that gap metabolism and the interaction of the metabolites with cell proteins were not essential for the BaP-induced modulation of alpha-hCG gene expression.Polycyclic aromatic hydrocarbons (PAHs) ~ are currently recognized as one of the major classes of environmental carcinogenic pollutants (1). Of the PAHs, benzo(a)pyrene (BaP) is Abbreviations used in this paper: AHH, aryl hydrocarbon hydroxylase; BaP benzo(a)pyrene; BF, 7,3-benzoflavone; ChaGo cells, human lung bronchogenic carcinoma cells; DMBA, dimethylbenzanthracene; alpha-hCG, the alpha subunit of human chorionic gonadotropin; alpha-hCG mRNA, alpha-hCG-specific mRNA sequences; PAHs, polycyclic aromatic hydrocarbons; SSC, 3 M NaC! and 0.3 M sodium acetate. accepted as the prototype (2, 3). Ectopic hormone and inappropriate gene expression are commonly found to be associated with neoplastic transformation of cells. BaP and several other members of the PAHs have been found to induce aryl hydrocarbon hydroxylase (AHH) in different mammalian cell systems (4). These inducers of AHH also enhance the expression of alpha-fetoprotein gene (5); activities of phospho...

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Experimental and clinical studies on the reproductive toxicology of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

Silbergeld

Mattison

1987

American J Industrial Med

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The reproductive toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been studied in animal models and in human populations. In animals, TCDD has a range of toxic effects on organs of the reproductive system in males and females, on hormone biochemistry, and on embryo-fetal development. These effects may involve in part an identified intracellular TCDD receptor and its association with the induction of microsomal cytochrome P-450-dependent monooxygenases in many organs. TCDD treatment increases activity of monooxygenase enzyme in liver and gonads of treated animals, but unlike other polycyclic aromatic hydrocarbons that are monooxygenase inducers, TCDD is not cytotoxic to any population of oocytes in the mature female mouse. Epidemiological studies of TCDD reproductive toxicity have been limited in design. There are some reports of adverse effects in the Seveso population and in children born to American veterans presumed to have been exposed to TCDD in Agent Orange during the Vietnam war. Occupational cohorts have not been found to show such paternally mediated effects of TCDD exposure.

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The Ah Receptor: Controlling Factor in the Induction of Drug-Metabolizing Enzymes by Certain Chemical Carcinogens and Other Environmental Pollutants

Cited by 52 publications

References 71 publications

Mouse cytochrome P₃-450: complete cDNA and amino acid sequence

Mouse cytochrome P₃-450: complete cDNA and amino acid sequence

Mechanism of benzo(a)pyrene induction of alpha-human chorionic gonadotropin gene expression in human lung tumor cells

Experimental and clinical studies on the reproductive toxicology of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

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The Ah Receptor: Controlling Factor in the Induction of Drug-Metabolizing Enzymes by Certain Chemical Carcinogens and Other Environmental Pollutants

Cited by 52 publications

References 71 publications

Mouse cytochrome P3-450: complete cDNA and amino acid sequence

Mouse cytochrome P3-450: complete cDNA and amino acid sequence

Mechanism of benzo(a)pyrene induction of alpha-human chorionic gonadotropin gene expression in human lung tumor cells

Experimental and clinical studies on the reproductive toxicology of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

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Product

Resources

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Mouse cytochrome P₃-450: complete cDNA and amino acid sequence

Mouse cytochrome P₃-450: complete cDNA and amino acid sequence