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Deiodination of thyroid hormone by human liver
T J Visser1, E Kaptein, O T Terpstra
1Department of Internal Medicine, Erasmus University Medical School, Rotterdam, The Netherlands.
The Journal of Clinical Endocrinology and Metabolism
|July 1, 1988
Summary
Human liver microsomes contain a single enzyme, similar to rat liver type I deiodinase, that efficiently clears thyroid hormones like reverse T3 (rT3) and T3 sulfate.
Area of Science:
- Biochemistry
- Endocrinology
- Molecular Biology
Background:
- The liver plays a crucial role in peripheral thyroid hormone metabolism, producing T3 from T4 and clearing rT3.
- Enzymatic mechanisms of thyroid hormone deiodination are not fully understood, with current knowledge primarily derived from rat studies.
- Understanding human liver deiodinase activity is essential for comprehending thyroid hormone regulation.
Purpose of the Study:
- To investigate the catalytic properties of iodothyronine deiodinase activity in human liver microsomes.
- To compare the characteristics of human liver deiodinase with known deiodinase types, particularly rat type I deiodinase.
- To elucidate the substrate specificity and kinetic properties of the enzyme responsible for thyroid hormone deiodination in the human liver.
Main Methods:
- Detailed characterization of catalytic properties of iodothyronine deiodinase activity in human liver microsomes.
- Substrate preference studies using various iodothyronines, including T4, T3, and rT3, and their sulfated forms.
- Kinetic analysis, including determination of reaction kinetics (ping-pong kinetics) and cofactor effects (dithiothreitol).
- Inhibition studies using propylthiouracil (PTU) to assess its effect on different deiodination reactions.
Main Results:
- Human liver deiodinase activity exhibits significant similarity to rat liver type I deiodinase.
- The enzyme preferentially deiodinates reverse T3 (rT3) approximately 400 times more efficiently than T4 or T3.
- Deiodination of sulfated substrates, such as T3 sulfate (T3S), is significantly faster (approx. 30-fold increase) than that of non-sulfated T3.
- Propylthiouracil (PTU) acts as an uncompetitive inhibitor with respect to substrate and competitive with dithiothreitol, indicating a single catalytic mechanism.
Conclusions:
- A single enzyme in human liver microsomes catalyzes both outer ring deiodination (ORD) and inner ring deiodination (IRD) of iodothyronines.
- This enzyme shares catalytic mechanisms and substrate specificity with the type I deiodinase found in rat liver.
- The findings provide crucial insights into the enzymatic basis of thyroid hormone metabolism in human liver.