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Thyroid hormones selectively modulate human alcohol dehydrogenase isozyme catalyzed ethanol oxidation
G Mårdh1, D S Auld, B L Vallee
1Center for Biochemical and Biophysical Sciences, Harvard Medical School, Boston, Massachusetts.
Biochemistry
|December 1, 1987
Summary
Thyroid hormones reversibly inhibit human alcohol dehydrogenase (ADH) classes I and II, affecting ethanol oxidation. This interaction identifies a novel binding site, impacting metabolic regulation.
Area of Science:
- Biochemistry
- Enzymology
- Endocrinology
Background:
- Human alcohol dehydrogenase (ADH) plays a crucial role in ethanol metabolism.
- Thyroid hormones are essential regulators of various physiological processes.
- The interaction between thyroid hormones and ADH activity is not fully understood.
Purpose of the Study:
- To investigate the inhibitory effects of thyroid hormones on human alcohol dehydrogenase (ADH) isozymes.
- To characterize the binding site and mechanism of inhibition by thyroid hormones on ADH.
- To explore the potential physiological implications of this inhibition.
Main Methods:
- Enzyme kinetics studies using purified human ADH isozymes (classes I, II, and III).
- Determination of inhibition constants (Ki) and mechanism of inhibition (mixed-type).
- Competitive binding assays with known ADH inhibitors and substrates.
Main Results:
- Thyroid hormones (triiodothyronine, thyroxine, triiodothyroacetic acid) are potent inhibitors of class I and II ADH, but not class III.
- Inhibition is mixed-type with respect to both NAD+ and ethanol.
- Thyroid hormones bind to a site overlapping with the 1,10-phenanthroline and testosterone binding sites.
Conclusions:
- Thyroid hormones represent a novel class of ADH inhibitors.
- The identified binding site suggests a regulatory role for thyroid hormones in ADH-catalyzed reactions.
- This inhibition may influence the metabolism of ethanol and other substrates processed by ADH.