MECHANISM-BASED INACTIVATION OF LACTOPEROXIDASE AND THYROID PEROXIDASE BY RESORCINOL DERIVATIVES

Humans are exposed to resorcinol derivatives in the environment throug h ground water, foods, food additives, drugs, and hair dyes. Epidemiol ogical studies have linked human exposure to phenolic compounds with t he thyroid disorder, goiter. The results presented here demonstrate th e suicide (mechanism-based) inactivation of thyroid peroxidase (TPO) a nd the closely related lactoperoxidase (LPO) by resorcinol derivatives . The evidence for this mechanism includes irreversible, hydrogen pero xide-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. 1 0 mol/mol of lactoperoxidase inactivated). The inactivation was specif ic for thyroid peroxidase and lactoperoxidase since the activity of ho rseradish peroxidase, myeloperoxidase, chloroperoxidase, or the pseudo peroxidase, 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, albe it at a much lower level, as were observed with horseradish peroxidase . The results are consistent with thyroid peroxidase- and lactoperoxid ase-catalyzed oxidation of resorcinol derivatives to reactive radical species that covalently bind to amino acid residues unique to these tw o 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 cyt ochrome c peroxidase. These results provide an explanation for the pot ency of resorcinol derivatives in the inhibition of LPO and TPO and th e 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.