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Direct Measurement of the Contributions of Type I and Type II 5'-Deiodinases to Whole Body Steady State 3,5,3'-Triiodothyronine Production from Thyroxine in the Rat*

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

Address all correspondence and requests for reprints to: Prof. Joseph J. DiStefano III, University of California, 4531 Boelter Hall, Los Angeles, California 90095-1596. E-mail: joed{at}cs.ucla.edu

Production of T₃ from T₄ in tissues is catalyzed by two 5'-deiodinases, type I (D1) and type II (D2), but the quantitative contribution of each pathway to whole body T₃ production is not well established. In the presence of propylthiouracil (PTU), D1, but not D2, can be effectively blocked, providing an experimental probe for addressing this problem. Decades ago, this approach provided indirect estimates ranging from 23–44% contribution by D2, based on plasma T₃ appearance rate comparisons (PAR₃ = PCR₃ [T₃]_p) in periodically T₄-injected athyreotic rats vs. controls. Two, more recent studies, using constant infusions of T₄ for replacement, achieved 22% and 65% estimates, respectively, from PAR₃ comparisons. We have revisited this problem more directly and precisely, with two major differences in experiment design. We used direct whole body steady state measurements of T₃ production, instead of indirect plasma-only data (PAR₃). We also used (euthyroid) physiological doses of both T₄ (0.9 µg/day·100 g BW) and T₃ (0.15 µg/day·100 g BW) for replacement in two thyroidectomized rat groups, instead of T₄ only, in a 7-day constant steady state, dual tracer infusion protocol. The first group also had chronically implanted 150-mg PTU pellets (TXR-PTU); the other had implanted 0.1 N NaOH placebo pellets (TXR-EU); each delivered their product at constant rates. A third euthyroid intact group was used as the controls. The completeness of D1 inhibition was ascertained in a fourth group, identically treated with 150-mg PTU pellets, in which negligible D1 activity was found in liver and kidney using labeled rT₃ as substrate for the 5'-D assays and minimal (1 mM) dithiothreitol as cofactor. In the TXR-PTU group, the percentage of T₄ converted to T₃ was 11.8%, compared with 23.4% (P < 0.0005) in the TXR-EU group, and 22.7% (P = NS) in controls. Thus, in euthyroid steady state, D2 contributes about half of the T₃ produced from T₄.

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