Submitted on May 31, 2002
Accepted on March 10, 2003
THYROID HORMONE PRODUCTION RATES IN RAT LIVER & INTESTINE IN VIVO: A NOVEL GRAPH THEORY/EXPERIMENTAL SOLUTION
Thuvan T. Nguyen1, Koen A. Mol1, and Joseph J. DiStefano III1*
1 Department of Computer Science and Medicine, University of California, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: joed{at}cs.ucla.edu.
We develop a novel graph-theoretic method for finding sufficient experimental conditions for discriminating and quantifying individual biomolecule production sources in distributed, inhomogeneous multisource systems in vivo and 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, in any species. Using a readily generalized graphical method called cut-set analysis, we show here that measurement of the steady state responses in several organs to three independent tracer infusions, two into blood and one directly into the organ(s) of interest, are together 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, finding 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 which include molecular interconversions at multiple sites.
