Our overall goal is to achieve a more comprehensive quantitative understanding of the mechanisms and physiological control of thyroid hormone production, distribution, metabolism and excretion. Particular emphasis is on the role of the enterohepatic system, and distribution and local metabolism rates of thyroid hormones in specific tissues as well as the whole animal. In our recent work in the rat, we have found very large hormone pools in the luminal contents of the intestine and, instead of being all excreta, we have shown that a portion of these pools are normally exchangeable with hormone in the rest of the body. This means these pools are involved in overall regulation of thyroid hormones in a more complex way than just as a pathway of unidirectional excretion in feces. Also, we have new evidence suggesting that more hormone enters the intestine via the blood than via the biliary pathway, contrary to current dogma, and that hormonal degradation processes, possibly interconversions, may be occurring in the bowel. In the coming years, we intend to further explore the ramifications of these new hypotheses. This includes a new series of studies in which bile flow will be diverted and resulting steady state hormone pool sizes in gut, plasma and other tissues, and hormone fluxes in feces, are each measured, to obtain in a more direct estimate of biliary versus net blood hormone transport fluxes to gut. Similar studies in the rat with and without bile diversion will be conducted under various pathological conditions, including: (a) hypo- and hyperthyroid states; (b) animals fed oral antibiotics, to inhibit normal deconjugation by intestinal bacteria -- and presumably reabsorption; and (c) fasting rats. Among the objectives here are to see how altered dietary states and abnormal thyroid states affect differential organ distribution of thyroid hormones, and to explore a dual role of intestinal bacteria in overall hormone regulation. The results may have significant clinical implications, if similar conditions exists in the human. We also intend to: (a) measure thyroid hormones in intestinal lymphatics, to test whether significant recycling of hormone occurs via this pathway; (b) directly quantify any deiodination of hormone that may occur in gut, in different portions of isolated gut preparations; (c) quantify any urinary and fecal excretion rates of thyroid hormone analogs Triac and Tetrac, also found in the intestine and feces under certain condition. Overall, we have chosen a constant infusion- to-steady-state approach, rather than single-injection pull doses for test-inputs, in nearly all of our experimental pull studies, because the results are far easier to interpret physiologically as well as mathematically.
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