Perinatal and chronic effects of flavonoids and polyphenolic compounds, contained in nutrition, on the thyroid hormone axis as well as endpoints and networks regulated by thyroid hormones
Zusammenfassung der Projektergebnisse
Plant secondary metabolites of the flavonoid and polyphenol class of ubiqutary dietary constituents are known to interfere with the endocrine system. In this project, their effect on thyroid hormone synthesis, distribution and action and possible side effects after in vivo application has been examined. Among many compounds screened, the isoflavonoid genistein and myricetin as well as the main flavonoid constituent of hops, xanthohumol, showed marked effects on the thyroid hormone axis. The isoflavonoid genistein, well known as estrogen receptor ligand and potent kinase inhibitor, proved to be a highly specific and potent competitor for T4 binding to the thyroid hormone distributor protein transthyretin. Transthyretin is contained in human serum and cerebrospinal fluid and represents in rodent sera the major thyroid hormone binding protein as rodents lack the high affinity binding protein TBG. Nanomolar concentrations of genistein completely display T4 from transthyretin leading to increased free thyroid hormone levels and subsequent alterations of thyroid hormone homeostasis such as increased urinary elimination and enhanced tissue exposure by hormone. Genistein also inhibits NIS function in thyrocytes, and in vivo application of genistein inhibits type 1 deiodinase and leads to decreased transcript levels of the TSH receptor and thyroperoxidase in mouse thyroids. Myricetin and xanthohumol inhibit human recombinant TPO activity. Xanthohumol administration in rats leads to alterations in thyroid hormone homeostasis such as increased TSH and T3 serum concentration, increased hepatic expression of thyroxin-binding globulin TBG, and decreased transthyretin and albumin transcript levels. Hepatic deiodinase activity was also increased while hepatic sulfotransferase-1A1 transcript but not its protein levels were decreased. In female livers, also the phase-2 conjugation enzyme UGT-1A1 was decreased. Probably, several of these effects are mediated by decreased expression of the constitutive androstane receptor CAR, whose transcript and protein levels were decreased. Together these studies indicate that several flavonoids and polyphenols interfere at several levels of the thyroid hormone axis with respect to synthesis, distribution and action. Some of the observed effects raise concern with respect to individuals with inadequate iodide supply, which might experience disturbed thyroid hormone homeostasis while the impact of xanthohumol-induced decrease in hepatic CAR expression and alterations observed in thyroid hormone homeostasis need further evaluation with respect to their potential beneficial effect on tumorigenesis. • Flavonoids and polyphenols exert specific effects on various components of thyroid hormone (TH) axis: TH biosynthesis (NIS, TPO), serum distributor proteins for TH /TTR), hepatic metabolism of TH (Dio, conjugation), and cellular action of TH. • Nanomolar xanthohumol concentrations stimulate, genistein inhibits NIS function in thyrocytes and might thus increase iodide bioavailability also in NIS expressing cancer cells. • Genistein and the synthetic F21388 inhibit human recombinant TPO activity, iodide might protect TPO from inactivation. • The isoflavonoid genistein, well known as ER-ligand and kinase inhibitor, is a very potent competitor for T4 binding to the serum and CSF thyroid hormone distributor protein transthyretin in nanomolar concentration, leading to increased free thyroid hormone levels and alterations of thyroid hormone homeostasis. • Xanthohumol administration in rats leads to marked alterations in expression of hepatic thyroid hormone distributor proteins, enzymes involved in conjugation and drug metabolism and the transcription factor CAR might mediate (some of) these effects. • Several flavonoids and polyphenols activate a T3-reporter gene in human hepatocarcinoma cells at µmolar concentrations. • Several risk groups with inadequate (nutritive) iodide supply or impaired thyroid function might experience adverse effects of inadequately high exposure to falvonoids and polyphenols. Epidemiological and pilot studies are required in humans and these potential risk groups. • Screening for potential antihormonal, especially antithyroidal effects of other flavonoids in the context of the REACH programme of EU has to be continued and in vivo data using adequate (transgenic) animal models are required. • More information on potential adverse interactions between various natural and synthetic nutritive flavonoid and polyphenolic compounds has to be collected and communicated to the interested public and to health authorities.
Projektbezogene Publikationen (Auswahl)
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(2005) Developmentally Regulated Thyroid Hormone Distributor Proteins in Marsupials, a Reptile and Fishes. Am J Physiol Regul Integr Comp Physiol R1264-72
Richardson SJ, Monk JA, Shepherdley CA, Ebbesson LOE, Sin F, Power DM, Frappell PB, Köhrle J, Renfree MB
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Xanthohumol stimulates iodide uptake in rat thyroidderived FRTL-5 cells. Mol Nutr.Food Res. 49 (9):832-836, 2005
B. Radovic, C. Schmutzler, and J. Köhrle
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(2006) Effects of isoflavonoids and other plantderived compounds on the hypothalamus-pituitary-thyroid hormone-axis. Maturitas; Nov 1;55 Suppl 1:S14-25
Hamann I, Seidlova-Wuttke D, Wuttke W, Köhrle J
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Genistein and other soya isoflavones are potent ligands for transthyretin in serum and cerebrospinal fluid. Br J Nutr. 95 (6):1171-1176, 2006
B. Radovic, B. Mentrup, and J. Kohrle
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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, 2007
C. Schmutzler, I. Gotthardt, P. J. Hofmann, B. Radovic, G. Kovacs, L. Stemmler, I. Nobis, A. Bacinski, B. Mentrup, P. Ambrugger, A. Gruters, L. K. Malendowicz, J. Christoffel, H. Jarry, D. Seidlova-Wuttke, W. Wuttke, and J. Köhrle
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Environment and endocrinology: the case of thyroidology. Ann.Endocrinol (Paris) 69 (2):116-122, 2008
J. Köhrle
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Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia. J Lipid Res. 2009 Feb;50(2):312-26
Kratzer A, Buchebner M, Pfeifer T, Becker TM, Uray G, Miyazaki M, Miyazaki-Anzai S, Ebner B, Chandak PG, Kadam RS, Calayir E, Rathke N, Ahammer H, Radovic B, Trauner M, Hoefler G, Kompella UB, Fauler G, Levi M, Levak-Frank S, Kostner GM, Kratky D
