Biosynthesis of 3-Iodothyronamine From T4 in Murine Intestinal Tissue

The endogenous metabolite 3-iodothyronamine (3-T(1)AM) induces strong hypothermia and bradycardia at pharmacological doses. Although its biosynthesis from thyroid hormone precursors appears likely, the sequence and sites of reactions are still controversial: studies in T-4-substituted thyroid cancer patients lacking functional thyroid tissue suggested extrathyroidal 3-T(1)AM production, whereas studies using labeled T-4 in mice indicated intrathyroidal formation. However, because the patients received T-4 orally, whereas the mice were injected ip, we hypothesized that 3-T(1)AM synthesis requires the intestinal passage of T-4. Using the everted gut sac model in combination with mass spectrometry, we demonstrate 3-T(1)AM production from T-4 in mouse intestine via several deiodination and decarboxylation steps. Gene expression analysis confirmed the expression of all 3 deiodinases as well as ornithine decarboxylase (ODC) in intestine. Subsequent experiments employing purified human ODC revealed that this enzyme can in fact mediate decarboxylation of 3,5-T-2 and T-4 to the respective thyronamines (TAMs), demonstrating that the intestine expresses the entire molecular machinery required for 3-T(1)AM biosynthesis. Interestingly, TAM production was strongly affected by the antithyroid treatment methimazole and perchlorate independently of thyroid status, limiting the validity of the respective mouse models in this context. Taken together, our data demonstrate intestinal 3-T(1)AM biosynthesis from T-4 involving decarboxylation through ODC with subsequent deiodination, and explain the apparent discrepancy between 3-T(1)AM serum levels in patients substituted orally and mice injected ip with T-4. Identifying ODC as the first enzyme capable of decarboxylating thyroid hormone, our findings open the path to further investigations of TAM metabolism on molecular and cellular levels.