Inhibition of Thyroid Peroxidase by Dietary Flavonoids

Abstract

Flavonoids are widely distributed in plant-derived foods and possess a variety of biological activities including antithyroid effects in experimental animals and humans. A structure-activity study of 13 commonly consumed flavonoids was conducted to evaluate inhibition of thyroid peroxidase (TPO), the enzyme that catalyzes thyroid hormone biosynthesis. Most flavonoids tested were potent inhibitors of TPO, with IC50 values ranging from 0.6 to 41 microM. Inhibition by the more potent compounds, fisetin, kaempferol, naringenin, and quercetin, which contain a resorcinol moiety, was consistent with mechanism-based inactivation of TPO as previously observed for resorcinol and derivatives. Other flavonoids inhibited TPO by different mechanisms, such as myricetin and naringin, showed noncompetitive inhibition of tyrosine iodination with respect to iodine ion and linear mixed-type inhibition with respect to hydrogen peroxide. In contrast, biochanin A was found to be an alternate substrate for iodination. The major product, 6,8-diiodo-biochanin A, was characterized by electrospray mass spectrometry and 1H-NMR. These inhibitory mechanisms for flavonoids are consistent with the antithyroid effects observed in experimental animals and, further, predict differences in hazards for antithyroid effects in humans consuming dietary flavonoids. In vivo, suicide substrate inhibition, which could be reversed only by de novo protein synthesis, would be long-lasting. However, the effects of reversible binding inhibitors and alternate substrates would be temporary due to attenuation by metabolism and excretion. The central role of hormonal regulation in growth and proliferation of thyroid tissue suggests that chronic consumption of flavonoids, especially suicide substrates, could play a role in the etiology of thyroid cancer.

Goitrogenic and estrogenic activity of soy isoflavones.

“…The first step is iodination of thyroglobulin tyrosyl residues, followed by oxidative coupling to yield T 4 and T 3 . Inhibition of porcine TPO activity is a mechanism common to many classes of synthetic antithyroid compounds (27)(28)(29)(30)(31) and naturally occurring flavonoids (32,33). Lactoperoxidase (LPO) is often used as a model for TPO, based on many shared structural and functional properties.…”

Antiatherogenic Properties of Naringenin, a Citrus Flavonoid

“…In a related study, Corvazier and Maclouf (17) demonstrated that naringenin (500 M) is an irreversible inhibitor of both LOX and COX pathways. Furthermore, naringenin has been shown to inhibit myeloperoxidase (MPO) (approximate IC 50 ‫ס‬ 150 M) (22). MPO secreted by macrophages and activated neutrophils is a potent catalyst of LDL oxidation in vitro and colocalizes with macrophages in human atherosclerotic lesions (40).…”

Green tea polyphenols inhibit testosterone production in rat Leydig cells

“…Its active components are reported to have several biological properties, including cancer chemoprevention, inhibition of tumour cell growth, antiviral and antiinflammatory activities [1], antioxidant activity [2,3] and inhibitory effects on several enzymes, such as aromatase [4,5], angiotensin converting enzyme [6] and thyroid peroxidase [7]. Dried leaves of C. sinensis contain polyphenols (30%-36%), principally flavanols, more commonly known as catechins [8].…”