Thyroid hormones selectively modulate human alcohol dehydrogenase isozyme catalyzed ethanol oxidation.
Thyroid hormones are potent, instantaneous, and reversible inhibitors of ethanol oxidation catalyzed by isozymes of class I and II human alcohol dehydrogenase (ADH). None of the thyroid hormones inhibits class III ADH. At pH 7.40 the apparent Ki values vary between 55 and 110 microM for triiodothyronine, 35 and greater than 200 microM for thyroxine, and 10 and 23 microM for triiodothyroacetic acid. The inhibition is of a mixed type toward both NAD+ and ethanol. The binding of the thyroid hormone triiodothyronine to beta 1 gamma 1 ADH is mutually exclusive with 1,10-phenanthroline, 4-methylpyrazole, and testosterone, identifying a binding site(s) for the thyroid hormones, which overlap(s) both the 1,10-phenanthroline site near the active site zinc atom and the testosterone binding site, the latter being a regulatory site on the gamma-subunit-containing isozymes and distinct from their catalytic site. The inhibition by thyroid hormones may have implications for regulation of ADH catalysis of ethanol and alcohols in the intermediary metabolism of dopamine, norepinephrine, and serotonin and in steroid metabolism. In concert with other hormonal regulators, e.g., testosterone, the rate of ADH catalysis is capable of being fine tuned in accord with both substrate and modulator concentrations.
Mårdh
G
G
Center for Biochemical and Biophysical Sciences, Harvard Medical School, Boston, Massachusetts.
Auld
D S
DS
Vallee
B L
BL
D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D013974:Thyroxine / Q000494:pharmacology*; D014284:Triiodothyronine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D007527:Isoenzymes; D014284:Triiodothyronine; C010642:3,3',5-triiodothyroacetic acid; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D013974:Thyroxine