The long term goal of this research is a more comprehensive quantitative understanding of the mechanisms and physiological control of thyroid hormone production, distribution and metabolism. These studies focus first on experimental determination of local metabolism in vivo of thyroid hormones (T4 and T3) in specific tissues of the rat. Three key unanswered questions are: (1) whether T3 found in specific tissues is generated locally from T4, or is it produced elsewhere; (2) how much T3 produced locally is degraded or otherwise altered at that same local tissue site (""""""""hidden pools"""""""") versus how much is free to exchange with the plasma pool and thus other tissues (""""""""exchangeable pools""""""""); and (3) whether T3, produced locally is processed differently than that arriving via exchange processes. This last (new) hypothesis has direct bearing on the question of thyroid hormone action, while the others have broader implications in understanding thyroid hormone metabolism in health and disease. The role of intestinal components of the enterohepatic system in whole-body thyroid hormone regulation also will be studied. These have been given very little attention for more than a decade, despite lingering controversies concerning their role in this system. The existence of pools of T3 and T4 of significant size in the gastrointestinal tract, free to return in significant quantity to systemic blood via reabsorption and recirculation, would identify these pools as exchangeable and therefore part of the internal mileau vis a vis thyroid hormone regulation. The experiments are based on direct measurements in all significant iodothyronine organ pools, including the gastrointestinal tract, generating a detailed profile of thyroid hormone and metabolite tissue distribution, molecular interconversion rates, and metabolic pathways of physiological or pathophysiological significance.
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