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Transthyretin and Endocrine Disruptors

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Abstract

In addition to binding thyroid hormones (THs), its endogenous ligands, transthyretin (TTR) can bind a large number of chemicals, including flavonoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and environmental pollutants. By binding to TTR, these chemicals have the potential to change TH homeostasis in plasma and interfere with the thyroid system, particularly in rodents and lower vertebrates. A structure–activity relationship of those chemicals that compete with TH for binding to TTR was found for several groups of chemicals. Owing to the binding specificity of these chemicals for TTR, a competitive binding assay for TH binding to TTR has been used to detect potent TH-disrupting chemicals in samples obtained from various environments. Recent advances in pharmacological and physiological research indicate that some chemicals that bind to TTR may have a chemotherapeutically beneficial effect on TTR-mediated amyloid fibril formation, whereas other chemicals that bind to TTR may have an adverse effect on retinoid homeostasis. Possible roles for the binding of chemicals to TTR are discussed.

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References

  • Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW (2004) Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J Med Chem 47:355–374

    Article  CAS  PubMed  Google Scholar 

  • Almeida MR, Macedo B, Cardoso I, Alves I, Valencia G, Arsequell G, Planas A, Saraiva MJ (2004) Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative. Biochem J 381:351–356

    Article  CAS  PubMed  Google Scholar 

  • Auf'mkolk M, Koehrle J, Hesch RD, Cody V (1986) Inhibition of rat liver iodothyronine deiodinase. Interaction of aurones with the iodothyronine ligand-binding site. J Biol Chem 261:11623–11630

    PubMed  Google Scholar 

  • Bellovino D, Morimoto T, Tosetti F, Gaetani S (1996) Retinol binding protein and transthyretin are secreted as a complex formed in the endoplasmic reticulum in HepG2 human hepatocarcinoma cells. Exp Cell Res 222:77–83

    Article  CAS  PubMed  Google Scholar 

  • Bergman A, Klasson-Wehler E, Kuroki H (1994) Selective retention of hydroxylated PCB metabolites in blood. Environ Health Perspect 102:464–469

    Article  CAS  PubMed  Google Scholar 

  • Berni R, Formelli F (1992) In vitro interaction of fenretinide with plasma retinol-binding protein and its functional consequences. FEBS Lett 308:43–45

    Article  CAS  PubMed  Google Scholar 

  • Berni R, Zanotti G, Sartori G, Monaco HL (1993) Plasma retinol-binding protein and its interaction with transthyretin. In: Livrea MA, Packer L (eds) Retinoids, Progress in Research and Clinical Applications, Marcel Dekker, New York, pp 91–102

    Google Scholar 

  • Brouwer A, van den Berg KJ (1986) Binding of a metabolite of 3,4,3′,4′-tetrachlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein complex carrying both retinol and thyroxin. Toxicol Appl Pharmacol 85:301–312

    Article  CAS  PubMed  Google Scholar 

  • Brouwer A, Reijnders PJH, Koeman JH (1989) Polychlorinated biphenyl (PCB)-contaminated fish induces vitamin A and thyroid hormone deficiency in the common seal (Phoca vitulina). Aquat Toxicol 15:99–105

    Article  CAS  Google Scholar 

  • Brouwer A, Klasson-Wehler E, Bokdam M, Morse DC, Traag WA (1990) Competitive inhibition of thyroxin binding to transthyretin by monohy-droxy metabolites of 3,4,3′,4′-tetrachlorobiphenyl. Chemosphere 20:1257–1262

    Article  CAS  Google Scholar 

  • Brouwer A, Morse DC, Lans MC, Schuur AG, Murk AJ, Klasson-Wehler E, Bergman Å, Visser TJ (1998) Interactions of persistent environmental organohalogens with thyroid hormone system: mechanisms and possible consequences for animal and human health. Toxicol Ind Health 14:59–84

    CAS  PubMed  Google Scholar 

  • Brouwer A, van den Berg KJ, Blaner WS, Goodman DS (1986) Transthyretin (prealbumin) binding of PCBS, a model for the mechanism of interference with vitamin A and thyroid hormone metabolism. Chemosphere 15:1699–1706

    Article  CAS  Google Scholar 

  • Brucker-Davis F (1998) Effects of environmental synthetic chemicals on thyroid function. Thyroid 8:827–856

    Article  CAS  PubMed  Google Scholar 

  • Chauhan KR, Kodavanti PR, McKinney JD (2000) Assessing the role of ortho-substitution on polychlorinated biphenyl binding to transthyretin, a thyroxine transport protein. Toxicol Appl Pharmacol 162:10–21

    Article  CAS  PubMed  Google Scholar 

  • Cheek AO, Kow K, Chen J, McLachlan JA (1999) Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environ Health Perspect 107:273–278

    Article  CAS  PubMed  Google Scholar 

  • Chopra IJ (1996) Nature, source, and relative biologic significance of circulating thyroid hormones. In: Braverman LE, Utiger RD (eds) Weiner and Ingbar's The Thyroid, 7th edn. Lippincott-Raven, Philadelphia, pp 111–124

    Google Scholar 

  • Ciszak E, Cody V, Luft JR (1992) Crystal structure determination at 2.3-Å resolution of human transthyretin-3′,5′-dibromo-2′,4,4′,6-tetrahydroxyaurone complex. Proc Natl Acad Sci USA 89:6644–6648

    Article  CAS  PubMed  Google Scholar 

  • DeVito M, Biegel L, Brouwer A, Brown S, Brucker-Davis F, Cheek AO, Christensen R, Colborn T, Cooke P, Crissman J, Crofton K, Doerge D, Gray E, Hauser P, Hurley P, Kohn M, Lazar J, McMaster S, McClain M, McConnell E, Meier C, Miller R, Tietge J, Tyl R (1999) Screening methods for thyroid hormone disruptors. Environ Health Perspect 107:407–414

    Article  CAS  PubMed  Google Scholar 

  • Fex G, Albertsson PA, Hansson B (1979) Interaction between prealbumin and retinol-binding protein studied by affinity chromatography, gel filtration and two-phase partition. Eur J Biochem 99:353–360

    Article  CAS  PubMed  Google Scholar 

  • Gonçalves I, Quintela T, Baltazar G, Almeida MR, Saraiva MJ, Santos CR (2008) Transthyretin interacts with metallothionein 2. Biochemistry 47:2244–2251

    Article  PubMed  Google Scholar 

  • Green NS, Foss TR, Kelly JW (2005) Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis. Proc Natl Acad Sci USA 102:14545–14550

    Article  CAS  PubMed  Google Scholar 

  • Hamann I, Seidlova-Wuttke D, Wuttke W, Köhrle J (2006) Effects of isoflavonoids and other plant-derived compounds on the hypothalamus–pituitary–thyroid hormone axis. Maturitas 55S:S14–S25

    Article  Google Scholar 

  • Heussen GA, Schefferlie GJ, Talsma MJ, van Til H, Dohmen MJ, Brouwer A, Alink GM (1993) Effects on thyroid hormone metabolism and depletion of lung vitamin A in rats by airborne particulate matter. J Toxicol Environ Health 38:419–434

    Article  CAS  PubMed  Google Scholar 

  • Houtman CJ, Cenijn PH, Hamers T, Lamoree MH, Legler J, Murk AJ, Brouwer A (2004) Toxicological profiling of sediments using in vitro bioassays, with emphasis on endocrine disruption. Environ Toxicol Chem 23:32–40

    Article  CAS  PubMed  Google Scholar 

  • Ishihara A, Sawatsubashi S, Yamauchi K (2003) Endocrine disrupting chemicals: interference of thyroid hormone binding to transthyretins and to thyroid hormone receptors. Mol Cell Endocrinol 199:105–117

    Article  CAS  PubMed  Google Scholar 

  • Johnson SM, Connelly S, Wilson IA, Kelly JW (2008) Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors. J Med Chem 51:260–270

    Article  CAS  PubMed  Google Scholar 

  • Johnson SM, Petrassi HM, Palaninathan SK, Mohamedmohaideen NN, Purkey HE, Nichols C, Chiang KP, Walkup T, Sacchettini JC, Sharpless KB, Kelly JW (2005) Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation. J Med Chem 48:1576–1587

    Article  CAS  PubMed  Google Scholar 

  • Julius RL, Farha OK, Chiang J, Perry LJ, Hawthorne MF (2007) Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores. Proc Natl Acad Sci USA 104:4808–4813

    Article  CAS  PubMed  Google Scholar 

  • Klabunde T, Petrassi HM, Oza VB, Raman P, Kelly JW, Sacchettini JC (2000) Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Biol 7:312–321

    Article  CAS  PubMed  Google Scholar 

  • Köhrle J, Fang SL, Yang Y, Irmscher K, Hesch RD, Pino S, Alex S, Braverman LE (1989) Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat. Endocrinology 125:532–537

    Article  PubMed  Google Scholar 

  • Köhrle J, Spanka M, Irmscher K, Hesch RD (1988) Flavonoid effects on transport, metabolism and action of thyroid hormones. In: Cody V, Middleton E, Harborne JB, Beretz A (eds), Plant Flavonoids in Biology and Medicine II: Biochemical, Cellular, and Medical Properties, Alan R Liss, New York, pp 323–340

    Google Scholar 

  • Lans MC, Klasson-Wehler E, Willemsen M, Meussen E, Safe S, Brouwer A (1993) Structure-dependent, competitive interaction of hydroxy-polychlorobiphenyls, -dibenzo-p-dioxins and -dibenzofurans with human transthyretin. Chem Biol Interact 88:7–21

    Article  CAS  PubMed  Google Scholar 

  • Lueprasitsakul W, Alex S, Fang SL, Pino S, Irmscher K, Köhrle J, Braverman LE (1990) Flavonoid administration immediately displaces thyroxine (T4) from serum transthyretin, increases serum free T4, and decreases serum thyrotropin in the rat. Endocrinology 126:2890–2895

    Article  CAS  PubMed  Google Scholar 

  • Malpeli G, Folli C, Berni R (1996) Retinoid binding to retinol-binding protein and the interference with the interaction with transthyretin. Biochim Biophys Acta 1294:48–54

    Article  PubMed  Google Scholar 

  • Mattsson K, Lehtinen KJ, Tana J, Härdig J, Kukkonen J, Nakari T, Engström C (2001) Effects of pulp mill effluents and restricted diet on growth and physiology of rainbow trout (Oncorhynchus mykiss). Ecotoxicol Environ Saf 49:144–154

    Article  CAS  PubMed  Google Scholar 

  • McCammon MG, Scott DJ, Keetch CA, Greene LH, Purkey HE, Petrassi HM, Kelly JW, Robinson CV (2002) Screening transthyretin amyloid fibril inhibitors: characterization of novel multiprotein, multiligand complexes by mass spectrometry. Structure 10:851–863

    Article  CAS  PubMed  Google Scholar 

  • McKinney JD, Chae K, Oatley SJ, Blake CC (1985) Molecular interactions of toxic chlorinated dibenzo-p-dioxins and dibenzofurans with thyroxine binding prealbumin. J Med Chem 28:375–381

    Article  CAS  PubMed  Google Scholar 

  • Meerts IATM, van Zanden JJ, Luijks EAC, van Leeuwen-Bol I, Marsh G, Jakobsson E, Bergman Å, Brouwer A (2000) Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. Toxicol Sci 56:95–104

    Article  CAS  PubMed  Google Scholar 

  • Mendel CM, Cavalieri RR, Köhrle J (1992) Thyroxine (T4) transport and distribution in rats treated with EMD 21388, a synthetic flavonoid that displaces T4 from transthyretin. Endocrinology 130:1525–1532

    Article  CAS  PubMed  Google Scholar 

  • Miller SR, Sekijima Y, Kelly JW (2004) Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. Lab Invest 84:545–552

    Article  CAS  PubMed  Google Scholar 

  • Miroy GJ, Lai Z, Lashuel HA, Peterson SA, Strang C, Kelly JW (1996) Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc Natl Acad Sci USA 93:15051–15056

    Article  CAS  PubMed  Google Scholar 

  • Morais-de-Sá E, Neto-Silva RM, Pereira PJ, Saraiva MJ, Damas AM (2006) The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin. Acta Crystallogr D Biol Crystallogr 62:512–519

    Article  PubMed  Google Scholar 

  • Morais-de-Sá E, Pereira PJ, Saraiva MJ, Damas AM (2004) The crystal structure of transthyretin in complex with diethylstilbestrol: a promising template for the design of amyloid inhibitors. J Biol Chem 279:53483–53490

    Article  PubMed  Google Scholar 

  • Munro SL, Lim CF, Hall JG, Barlow JW, Craik DJ, Topliss DJ, Stockigt JR (1989) Drug competition for thyroxine binding to transthyretin (prealbumin): comparison with effects on thyroxine-binding globulin. J Clin Endocrinol Metab 68:1141–1147

    Article  CAS  PubMed  Google Scholar 

  • Murata T, Yamauchi K (2007) 3,3′,5-Triiodo-l-thyronine-like activity in effluents from domestic sewage treatment plants detected by in vitro and in vivo bioassays. Toxicol Appl Pharmacol 226:309–317

    Article  PubMed  Google Scholar 

  • Oza VB, Smith C, Raman P, Koepf EK, Lashuel HA, Petrassi HM, Chiang KP, Powers ET, Sachettinni J, Kelly JW (2002) Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors. J Med Chem 45:321–332

    Article  CAS  PubMed  Google Scholar 

  • Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC, Kelly JW (1998) Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc Natl Acad Sci USA 95:12956–12960

    Article  CAS  PubMed  Google Scholar 

  • Petrassi HM, Johnson SM, Purkey HE, Chiang KP, Walkup T, Jiang X, Powers ET, Kelly JW (2005) Potent and selective structure-based dibenzofuran inhibitors of transthyretin amyloidogenesis: kinetic stabilization of the native state. J Am Chem Soc 127:6662–6671

    Article  CAS  PubMed  Google Scholar 

  • Purkey HE, Dorrell MI, Kelly JW (2001) Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma. Proc Natl Acad Sci USA 98:5566–5571

    Article  CAS  PubMed  Google Scholar 

  • Purkey HE, Palaninathan SK, Kent KC, Smith C, Safe SH, Sacchettini JC, Kelly JW (2004) Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity. Chem Biol 11:1719–1728

    Article  CAS  PubMed  Google Scholar 

  • Raghu P, Reddy GB, Sivakumar B (2004) Inhibition of transthyretin amyloid fibril formation by 2,4-dinitrophenol through tetramer stabilization. Arch Biochem Biophys 400:43–47

    Article  Google Scholar 

  • Refai E, Dekki N, Yang SN, Imreh G, Cabrera O, Yu L, Yang G, Norgren S, Rössner SM, Inverardi L, Ricordi C, Olivecrona G, Andersson M, Jörnvall H, Berggren PO, Juntti-Berggren L (2005) Transthyretin constitutes a functional component in pancreatic b-cell stimulus-secretion coupling. Proc Natl Acad Sci USA 102:17020–17025

    Article  CAS  PubMed  Google Scholar 

  • Rickenbacher U, McKinney JD, Oatley SJ, Blake CC (1986) Structurally specific binding of halogenated biphenyls to thyroxine transport protein. J Med Chem 29:641–648

    Article  CAS  PubMed  Google Scholar 

  • Robbins J (1996) Thyroid hormone transport proteins and the physiology of hormone binding. In: Braverman LE, Utiger RD (eds) Weiner and Ingbar's The Thyroid, 7th edn. Lippincott-Raven, Philadelphia, pp 96–110

    Google Scholar 

  • Schmutzler C, Gotthardt I, Hofmann PJ, Radovic B, Kovacs G, Stemmler L, Nobis I, Bacinski A, Mentrup B, Ambrugger P, Grüters A, Malendowicz LK, Christoffel J, Jarry H, Seidlovà-Wuttke D, Wuttke W, Köhrle J (2007) Endocrine disruptors and the thyroid gland-a combined in vitro and in vivo analysis of potential new biomarkers. Environ Health Perspect 115(Suppl 1):77–83

    Article  PubMed  Google Scholar 

  • Schröder-van der Elst JP, Smit JW, Romijn HA, van der Heide D (2003) Dietary flavonoids and iodine metabolism. Biofactors 19:171–176

    Article  PubMed  Google Scholar 

  • Schröder-van der Elst JP, van der Heide D, Köhrle J (1991) In vivo effects of flavonoid EMD 21388 on thyroid hormone secretion and metabolism in rats. Am J Physiol 261:E227–E232

    PubMed  Google Scholar 

  • Schröder-van der Elst JP, van der Heide D, Rokos H, Köhrle J, Morreale de Escobar G (1997) Different tissue distribution, elimination, and kinetics of thyroxine and its conformational analog, the synthetic flavonoid EMD 49209 in the rat. Endocrinology 138:79–84

    Article  PubMed  Google Scholar 

  • Schreiber G, Richardson SJ (1997) The evolution of gene expression, structure and function of transthyretin. Comp Biochem Physiol B Biochem Mol Biol 116:137–160

    Article  CAS  PubMed  Google Scholar 

  • Shidoji Y, Muto Y (1977) Vitamin A transport in plasma of the non-mammalian vertebrates: isolation and partial characterization of piscine retinol-binding protein. J Lipid Res 18:679–691

    CAS  PubMed  Google Scholar 

  • Smith TJ, Davis FB, Deziel MR, Davis PJ, Ramsden DB, Schoenl M (1994) Retinoic acid inhibition of thyroxine binding to human transthyretin. Biochim Biophys Acta 1199:76–80

    CAS  PubMed  Google Scholar 

  • Van den Berg KJ (1990) Interaction of chlorinated phenols with thyroxine binding sites of human transthyretin, albumin and thyroid binding globulin. Chem Biol Interact 76:63–75

    Article  CAS  PubMed  Google Scholar 

  • Van den Berg KJ, van Raaij JA, Bragt PC, Notten WR (1991) Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo. Arch Toxicol 65:15–19

    Article  CAS  PubMed  Google Scholar 

  • van der Heide D, Kastelijn J, Schröder-van der Elst JP (2003) Flavonoids and thyroid disease. Biofactors 19:113–119

    Article  PubMed  Google Scholar 

  • Vos JG, Dybing E, Greim HA, Ladefoged O, Lambré C, Tarazona JV, Brandt I, Vethaak AD (2000) Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation. Crit Rev Toxicol 30:71–133

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Nelson JC, Wilcox RB (1999) Salsalate and salicylate binding to and their displacement of thyroxine from thyroxine-binding globulin, transthyretin, and albumin. Thyroid 9:359–364

    Article  CAS  PubMed  Google Scholar 

  • White JT, Kelly JW (2001) Support for the multigenic hypothesis of amyloidosis: the binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro. Proc Natl Acad Sci USA 98:13019–13024

    Article  CAS  PubMed  Google Scholar 

  • Yamauchi K, Ishihara A (2006) Thyroid system-disrupting chemicals: interference with thyroid hormone binding to plasma proteins and the cellular thyroid hormone signaling pathway. Rev Environ Health 21:229–251

    CAS  PubMed  Google Scholar 

  • Yamauchi K, Ishihara A, Fukazawa H, Terao Y (2003) Competitive interactions of chlorinated phenol compounds with 3,3′,5-triiodothyronine binding to transthyretin: detection of possible thyroid-disrupting chemicals in environmental waste water. Toxicol Appl Pharmacol 187: 110–117

    Article  CAS  PubMed  Google Scholar 

  • Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB (2005) Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436:356–362

    Article  CAS  PubMed  Google Scholar 

  • Zanotti G, Malpeli G, Berni R (1993) The interaction of N-ethyl retinamide with plasma retinol-binding protein (RBP) and the crystal structure of the retinoid-RBP complex at 1.9-Å resolution. J Biol Chem 268:24873–24879

    CAS  PubMed  Google Scholar 

  • Zanotti G, Berni R (2004) Plasma retinol-binding protein: structure and interactions with retinol, retinoids, and transthyretin. Vitam Horm 69:271–295

    Article  CAS  PubMed  Google Scholar 

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Yamauchi, K., Ishihara, A. (2009). Transthyretin and Endocrine Disruptors. In: Richardson, S.J., Cody, V. (eds) Recent Advances in Transthyretin Evolution, Structure and Biological Functions. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00646-3_10

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