Mechanism-based inactivation of lactoperoxidase and thyroid peroxidase by resorcinol derivatives.
Humans are exposed to resorcinol derivatives in the environment through ground water, foods, food additives, drugs, and hair dyes. Epidemiological studies have linked human exposure to phenolic compounds with the thyroid disorder, goiter. The results presented here demonstrate the suicide (mechanism-based) inactivation of thyroid peroxidase (TPO) and the closely related lactoperoxidase (LPO) by resorcinol derivatives. The evidence for this mechanism includes irreversible, hydrogen peroxide-dependent loss of enzymatic activity by kinetics consistent with a suicide mechanism, concomitant with changes in the visible spectrum of the prosthetic heme group and covalent binding of resorcinol (ca. 10 mol/mol of lactoperoxidase inactivated). The inactivation was specific for thyroid peroxidase and lactoperoxidase since the activity of horseradish peroxidase, myeloperoxidase, chloroperoxidase, or the pseudoperoxidase, metmyoglobin, was unaffected by incubation with resorcinol. The enzymatic oxidation of resorcinol by lactoperoxidase was linked to inactivation since the same products were observed spectrally, albeit at a much lower level, as were observed with horseradish peroxidase. The results are consistent with thyroid peroxidase- and lactoperoxidase-catalyzed oxidation of resorcinol derivatives to reactive radical species that covalently bind to amino acid residues unique to these two enzymes. The oxidation of thyroid peroxidase and lactoperoxidase by hydrogen peroxide produces catalytic intermediates containing unpaired electron density on amino acid residues similar to that seen with cytochrome c peroxidase. These results provide an explanation for the potency of resorcinol derivatives in the inhibition of LPO and TPO and the goitrogenic responses observed in humans and animals. The widespread occurrence of resorcinol derivatives in the environment suggests that exposure to these compounds may cause thyroid dysfunction in humans.
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National Center for Toxicological Research, Jefferson, Arkansas 72079.
Doerge
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D004305:Dose-Response Relationship, Drug; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007784:Lactoperoxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D010544:Peroxidases / Q000187:drug effects; D012118:Resorcinols / Q000494:pharmacology*
D012118:Resorcinols; D007784:Lactoperoxidase; D010544:Peroxidases; D007453:Iodide Peroxidase