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Via Poison Dioxin. |
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General Note: Dioxin causes expensive disabilities like ADD/ADHD. Eliminate endocrine disruptors like dioxin and save $4,000/year/household on unnecessarily high Medicare and private medical insurance, disability taxes and extra income taxes to make up for taxes not paid by unnecessarily disabled people. |
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Ref. 15 EDSTAC, P450 Endocrine Detox System, Dr. Dennison Both the toxic metal lead and dioxin affect the P450 Detox System which if suppressed (lead) or induced to the point of overload, cannot convert ("break down") other toxic substances found in incinerator ash and other locations. EDSTAC. US EPA, Endocrine Disrupter Screening and Testing Advisory Committee. Dioxins are one group of many endocrine disruptors that are of concern by the EPA. Dioxins disrupt multiple endocrine systems including the P450 Detox System. Mechanism of Dioxin Action, P450 System: Molecular Mechanism of Dioxin Action: Dr. M.S. Denison, Researcher: http://dioxins-r-us.ucdavis.edu/TCDDAhR.HTML Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated dibenzo-p-dioxins, biphenyls, dibenzofurans, and related compounds represent a diverse group of persistent, widespread environmental contaminants. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin), the most biologically-active and toxic member of this class of compounds produces a wide variety of species- and tissue-specific effects (1,2) including: tumor promotion, immuno- hepato- and dermal toxicity, lethality, birth defects, endocrine disruption and induction of numerous enzymes, most notably that of microsomal cytochrome P4501A1 and its associated monooxygenase activity, aryl hydrocarbon hydroxylase (AHH) (1,2). The P4501A1 isozyme contributes to the metabolic activation and detoxification of polycyclic aromatic hydrocarbons, many of which are carcinogens (3). The induction of hepatic AHH activity is perhaps the best studied of the biochemical effects resulting from exposure to TCDD and related HAHs (4,5). Early experiments examining the induction of AHH activity by a series of halogenated dibenzo-p-dioxin and dibenzofuran congeners resulted in the identification of a specific receptor which bound these compounds saturably and with high affinity. Qualitative structure-activity relationship studies revealed that the ability of a compound to bind to this receptor was well correlated not only with its ability to induce AHH activity (1,2,6) but also its ability to induce toxic effects, such as thymic involution, wasting and epidermal keratinization (1,2,6,7), suggesting that the receptor also mediates the toxicity of these compounds. This TCDD receptor has been identified and characterized in a wide variety of species and tissues (8,9) and has been designated as the aromatic hydrocarbon receptor (AhR). Induction of hepatic P450IA1-dependent AHH activity has been utilized as a model system to examine the molecular mechanism of action of HAHs. The current model for the AhR-dependent P4501A1 induction mechanism (above) is in several ways similar to that described for some steroid hormone receptors and steroid-responsive genes (10,11). The unliganded AhR complex exists in the cytosol complexed with at least three additional proteins (12). Following high affinity ligand (TCDD) binding, the TCDD:AhR complex undergoes a poorly defined process of transformation, during which hsp90 (a heat shock protein of 90 kDa) and other proteins appear to dissociate from the TCDD:AhR complex, the AhR complex acquires the ability to bind to DNA with high affinity and transformed TCDD:AhR complexes subsequently accumulate within the nucleus (12-16). High affinity DNA binding of the AhR complex appears to require its association with at least one additional protein, the Ah receptor nuclear translocator (ARNT) protein (17-20). The binding of these transformed heteromeric TCDD:AhR complexes to specific DNA sequences (Dioxin Responsive Elements (DREs)) adjacent to the cytochrome P4501A1 (CYP1A1) gene leads to DNA bending, chromatin disruption, increased promoter accessibility and increased rates of transcription initiation of the CYP1A1 gene with the subsequent accumulation of cytochrome P450IA1-specific mRNA (4,21-27). The presence of the AhR complex in a wide variety of species and tissues and with its ability to act as a ligand-dependent transactivator of gene expression suggests that many of the toxic and biological effects of HAHs result from differential alteration of gene expression in susceptible cells. Dr. Dennison's References: 1. Poland,A. and Knutson,J.C. (1982) 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity, Ann. Rev. Pharmacol. Toxicol. 22, 517-554. 2. Safe,S.H. (1986) Comparative toxicology and mechanism of action of polychlorinated dibenzo-p-dioxins and dibenzofurans, Ann. Rev. Pharmacol.Toxicol. 26, 371-399. 3. Gelboin,H.V. (1980) Benzo[a]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes, Physiol. Rev. 60, 1107-1166. 4. Whitlock,J.P. (1986) The regulation of cytochrome P-450 gene expression, Ann. Rev. Pharmacol. Toxicol. 26, 333-369. 5. Whitlock,J.P.,Jr. (1990) Genetic and Molecular Aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin action, Ann. Rev. Pharmacol. Toxicol. 30, 251-277. 6. Goldstein,J.A. and Safe,S. (1989) Mechanism of action and structure-activity relationships for the chlorinated dibenzo-p-dioxins and related compounds, in: Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products (Kimbrough,R.D. and Jensen,J., eds), pp. 239-293, Elsevier Science Pub, Amsterdam. 7. Knutson,J.C. and Poland,A. (1980) Keratinization of mouse teratoma cell line XB produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin: an in vitro model of toxicity, Cell 22, 27-36. 8. Denison,M.S. and Wilkinson,C.F. (1985) Identification of the Ah receptor in selected mammalian species and induction of aryl hydrocarbon hydroxylase, Eur. J. Biochem. 147, 439-435. 9. Denison,M.S., Wilkinson,C.F. and Okey,A.B. (1986) Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin: comparative studies in mammalian and nonmammalian species, Chemosphere 15, 1665-1672. 10. Yamamoto,K.R. (1985) Steroid receptor regulated transcription of specific genes and gene networks, Ann. Rev. Genet. 19, 209-252. 11. Carson-Jurica,M.A., Schrader,W.T. and O'Malley,B.M. (1990) Steroid receptor family: structure and functions, Endo. Rev. 11, 201-214. 12. Perdew,G.H. (1992) Chemical cross-linking of the cytosolic and nuclear forms of the Ah receptor in hepatoma line 1c1c7, Biochem. Biophys. Res. Comm. 182, 55-62. 13. Perdew,G.H. and Poland,A. (1988) Purification of the Ah receptor from C57BL/6J mouse liver, J. Biol. Chem., 263, 9848-9852. 14. Henry,E.C., Rucci,G.and Gasiewicz,T.A. (1989) Characterization of multiple forms of the Ah receptor: comparison of species and tissues, Biochem. 28, 6430-6440. 15. Whitlock,J.P., Jr. and Galeazzi,D.R. (1984) 2,3,7,8-Tetrachlorodibenzo-p-dioxin receptors in mouse hepatoma cells: nuclear location and strength of nuclear binding, J. Biol. Chem. 259, 980-985. 16. Henry,E.C. and Gasiewicz,T.A. (1993) Transformation of the aryl hydrocarbon receptor to a DNA-binding form is accompanied by release of the 90 kDa heat-shock protein and increased affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin, Biochem. J. 294, 95-101. 17. Dolwick,K.M., Schmidt,J.V., Carver,L.A., Swanson,H.I. and Bradfield,C.A. (1993) Cloning and expression of human Ah receptor cDNA, Molec. Pharm. 44, 911-917. 18. Whitelaw,M., Pongratz,I., Wilhelmsson,A., Gustafsson,J-A. and Poellinger,L. (1993) Ligand-dependent recruitment of the arnt coregulator determines DNA recognition by the dioxin receptor, Molec. Cell.Biol. 13, 2504-2514. 19. Probst,M.R., Reisz-Porszasz,S., Agbunag,R.V., Ong,M.S. and Hankinson,O., (1993) Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action, Molec. Pharmacol. 44, 511-518. 20. Hoffman,E.C., Reyes,H., Chu,F-F., Sander,F., Conley,L.H., Brooks,B.A. and Hankinson,O. (1991) Cloning of a factor required for activity of the Ah (dioxin) receptor, Science 252, 954-958. 21. Denison,M.S., Fisher,J.M. and Whitlock,J.P.,Jr. (1988) Inducible, receptor-dependent protein-DNA interactions at a dioxin-responsive transcriptional enhancer, Proc.Natl. Acad. Sci. 85, 2528-2532. 22. Elferink,C.J. and Whitlock,J.P.,Jr. (1990) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-inducible, Ah receptor-mediated bending of enhancer DNA, J. Biol. Chem. 265, 5718-5721. 23. Morgan,J.E. and Whitlock,J.P.,Jr. (1992) Transcription-dependent and transcription-independent nucleosome disruption induced by dioxin, Proc. Natl. Acad. Sci. USA 89,11622-11626. 24. Durrin,L.K. and Whitlock,J.P.,Jr. (1989) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-inducible aryl hydrocarbon receptor-mediated change in CYP1A1 chromatin structure occurs independent of transcription, Mol.Cell. Biol. 9:5733-5737. 25. Wu,L. and Whitlock,J.P.Jr., (1992) Mechanism of dioxin action: Ah receptor-mediated increase in Promoter accessibility in vivo, Proc. Natl.Acad. Sci. 89, 4811-4815. 26. Denison,M.S., Fisher,J.M. and Whitlock,J.P.,Jr. (1988) The DNA recognition site for the dioxin-Ah receptor complex: nucleotide sequence and functional analysis, J. Biol. Chem. 263, 17221-17224. 27. Denison,M.S., Fisher,J.M.and Whitlock,J.P.,Jr. (1989) Protein-DNA interactions at recognition sites for the dioxin-Ah receptor complex, J. Biol. Chem. 264, 16478-16482. Revised 03/03/2000, Additional P450 detox enzyme information can be found with the National Library of Medicine site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pub Med Main Pages: | Endocrine Disruption Briefing Book | | Attachment List, ED Briefing Book | Attachment Pages: | ADD/ADHD | | Children-Developmental Damage | | Symptoms, Physical-Cognitive | | Diabetes | | Porphyria-LiverSpots | | Porphyria-Suppressed Detox | | Thyroid Disruptions | | Cancer, et al | | Cancer, et al | | Bethune School Dioxin | | Whitehouse School Scandal | | Belgium Govt. Topples | | 314 Toxic Chemicals | | 3700 Porphyrinogenic Chemicals | | Professional Dioxin Reports | | Industry View Dioxin | | Dust Carries Toxics-Dioxin | Cost Estimates, For Medical & Social Problems: | 5 most costly dioxin diseases Overview | Additional Overview Info: | PCB Toxicity by CDC | | 48% Graduation Rate Jax FL | | EDSTAC | Send questions to: | [email protected] | | [email protected] | |