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ORIGINAL ARTICLE

Generation of Oxygen Free Radicals in Thyroid Cells and Inhibition of Thyroid Peroxidase

Masahiro Sugawara^1,*, Yoshinobu Sugawara^*, Katherine Wen^* and Cecilia Giulivi

^* The Division of Endocrinology and Metabolism, West Los Angeles Veterans Affairs Medical Center and the Department of Medicine, University of California, Los Angeles, School of Medicine, Los Angeles, California 90073; and
The Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033

We examined whether superoxide (O₂^-) is produced as a precursor of hydrogen peroxide (H₂O₂) in cultured thyroid cells using the cytochrome c method and the electron paramagnetic resonance (EPR) method. No O₂^- or its related radicals was detected in thyroid cells under the physiological condition. The presence of quinone, 2,3-dimethoxy-l-naphthoquinone (DMNQ), or 2-methyl-1, 4-naphthoquinone (menadione), in the medium produced O₂^- and hydroxyl radicals (OH•); the amount of H₂O₂ generation was also increased. Incubation of follicles with DMNQ or menadione inhibited iodine organification (a step of thyroid hormone formation) and its catalytic enzyme, thyroid peroxidase (TPO). This inhibition should be caused by reactive oxygen species because the two quinones, particularly DMNQ, exert their effect through the generation of reactive oxygen species. It is speculated that the site-specific inactivation of TPO might have occurred at the heme-linked histidine residue of the TPO molecule, a critical amino acid for enzyme activity because OH• (vicious free radicals) can be formed at the iron-linked amino acid. TPO mRNA level and electrophoretic mobility of TPO were not inhibited by quinones. Our study suggests that thyroid H₂O₂ is produced by divalent reduction of oxygen without O₂^- generation. If thyroid cells happen to be exposed to significant amount of reactive oxygen species, TPO and subsequent thyroid hormone formation are inhibited.

Key Words: thyroid peroxidase • superoxide • hydrogen peroxide • quinones • thyroid cells

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