Exp Clin Endocrinol Diabetes 2015; 123 - P12_22
DOI: 10.1055/s-0035-1547756

Towards the intestinal biosynthesis of 3-iodothyronamine

C Höfig 1, T Wünsch 2, I Lehmphul 3, E Rijntjes 4, H Daniel 5, U Schweizer 6, J Mittag 7, J Köhrle 8
  • 1Karolinska Institutet, Department of Cell & Molecular Biology, Sweden; Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin, Germany; Department of Cell & Molecular Biology
  • 2Karolinska Institutet, Department of Cell & Molecular Biology, Sweden
  • 3Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin, Germany
  • 4Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin
  • 5Ziel Research Center of Nutrition and Food Science, Abteilung Biochemie, Technische Universität München
  • 6Rheinische Friedrich-Wilhelms-Universität Bonn; Institut für Biochemie und Molekularbiologie
  • 7Universität Lübeck; Cbbm/Medi; Mfc1
  • 8Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin, Germany; Institut für Experimentelle Endokrinologie

Introduction: 3-Iodothyronamine (3-T1AM) is an endogenous metabolite, which at pharmacological doses induces a rapid drop in body temperature and heart rate. Although its biosynthesis from thyroid hormone appears likely, the exact mechanism is still controversial: our previous study in thyroxine (T4)-substituted thyroid cancer patients lacking functional thyroid tissue, which show normal levels of 3-T1AM, suggested extrathyroidal 3-T1AM production, while other studies using hypothyroid mice substituted with labeled T4 showed no production of 3-T1AM, indicating intrathyroidal formation. However, since the patients received T4 orally whereas the mice were i.p. injected, we hypothesized that intestinal passage might be an important step in 3-T1AM biosynthesis.

Methods: We studied uptake and metabolism of T4 as a potential precursor of 3-T1AM using the ex vivo everted mouse gut sac model and LC-MS/MS. To unravel possible mechanisms involved in 3-T1AM biosynthesis, we used gene expression analysis and an in vitro decarboxylation assay with purified enzyme. To test the relevance of intestinal passage for 3-T1AM production in vivo, we used hypothyroid mice (methimazole (MMI)/sodium perchlorate) and treated them orally with T4 to study the resulting changes in serum thyroid hormones and intestinal gene expression.

Results: We found that mouse intestinal tissue can produce 3-T1AM from T4 via several deiodination and decarboxylation steps. In vitro experiments identified ornithine decarboxylase (ODC) as an enzyme capable of decarboxylating 3,5-T2 as well as T4. Subsequent gene expression analysis showed that besides ODC all three deiodinases (DIO) are also expressed in mouse intestine. Further studies in MMI/perchlorate-induced hypothyroid mice revealed that intestinal DIO1 and ODC are significantly down-regulated by the treatment compared to control intestine or T4 replacement.

Conclusions: Our data show that intestinal 3-T1AM biosynthesis from T4 is possible, and identifies ODC as the first enzyme catalyzing decarboxylation of thyroid hormones to 3-T1AM. MMI/perchlorate treatment in vivo, however, affects gene expression independently of thyroid hormone levels, suggesting that antithyroid drugs may be of limited value to study thyronamine biosynthesis in vivo.