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Thyroid hormone production rates in rat liver and intestine in vivo: a novel graph theory and experimental solution

Biocybernetics Laboratory, Departments of Computer Science and Medicine, University of California Los Angeles, Los Angeles, California 90095-1596

Submitted 31 May 2002 ; accepted in final form 10 March 2003

We develop a novel method for finding sufficient experimental conditions for discriminating and quantifying individual biomolecule production sources in distributed, inhomogeneous multisource systems in vivo, and we apply it experimentally to a complex, unsolved problem in endocrinology. The majority of hormonal triiodothyronine (T₃) is produced from prohormone thyroxine (T₄) in numerous nonthyroidal organs and, with one exception, the T₃ production rate has not been fully resolved in any single extrathyroidal organ of any species. Using a readily generalized graphic method called cut-set analysis, we show here that measured steady-state responses in several organs to three independent tracer infusions, two into blood and one directly into the organ(s) of interest, are sufficient to resolve this problem for organs fully accessible to direct infusion in vivo. We evaluated local T₃ production in rat liver and intestine, which also required T₃ bile flux measurements, and we found that liver produces 31% and whole intestine 6% of whole body T₃ from T₄. With thyroidal production included, liver contributes 15% and intestine 3% of whole rat T₃ production. This new methodology is broadly applicable, especially to biosystems that include molecular interconversions at multiple sites.

multisource triiodothyronine production; cut-set analysis; local organ hormone production rates; thyroid hormone interconversion; intraduodenal-intraileal infusion; bile hormone flux; steady-state kinetics; inhomogeneous multisource biosystems