Inhibition of peroxidase-catalyzed reactions by arylamines: mechanism for the anti-thyroid action of sulfamethazine.
Sulfonamide antibiotics, typified by sulfamethazine (SMZ), are widely used in veterinary practice. Sulfonamide residues in milk and meat products are of regulatory concern since SMZ is a thyroid carcinogen in rodents and sulfonamide-induced hypersensitivity reactions, including hypothyroidism, have been reported in humans. SMZ and other primary arylamines inhibited iodination reactions catalyzed by thyroid peroxidase (TPO) and the closely related lactoperoxidase (LPO). Inhibition of LPO-catalyzed triiodide ion formation by SMZ and other primary arylamines was complex as both apparent Km and Vmax values were affected, but consistent with a rapid equilibrium binding mechanism. The apparent Ki for SMZ inhibition of TPO- and LPO-catalyzed iodide ion oxidation was approximately 0.42 and 0.11 mM, respectively. The corresponding Ki values for a series of para-substituted anilines correlated with the ease of one-electron N-oxidation as measured by ionization potentials determined from semiempirical molecular orbital calculations. The aniline derivatives containing electron-donating substituents (e.g., p-CH3, p-OEt, p-Cl) were converted by LPO to colored products characteristic of one-electron oxidation. However, sulfonamides were not consumed in such reactions nor were any N-oxygenated derivatives formed in the absence of ascorbate (e.g., hydroxylamino, nitroso, nitro, azoxy). These observations suggest that the primary mechanism for sulfonamide-induced hypothyroidism is reversible inhibition of TPO-mediated thyroid hormone synthesis and not the formation and covalent binding of reactive N-oxygenated metabolites. These results are consistent with a hormonal mechanism for SMZ-induced thyroid carcinogenesis mediated by thyroid-stimulating hormone (TSH).(ABSTRACT TRUNCATED AT 250 WORDS)
Doerge
D R
DR
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Decker
C J
CJ
D000588:Amines / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors; D007784:Lactoperoxidase / Q000037:antagonists & inhibitors; D010544:Peroxidases / Q000037:antagonists & inhibitors*; D013418:Sulfamethazine / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects* / Q000201:enzymology
D000588:Amines; D002273:Carcinogens; D013418:Sulfamethazine; D007784:Lactoperoxidase; D010544:Peroxidases; D007453:Iodide Peroxidase