Evidence of Chemical Stimulation of Hepatic Metabolism by an Experimental Acetanilide (FOE 5043) Indirectly Mediating Reductions in Circulating Thyroid Hormone Levels in the Male Rat

N-(4-Fluorophenyl)-N-(1-methylethyl)-2-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide(FOE 5043) is a new acetanilide-type herbicide undergoing regulatorytesting. Previous work in this laboratory suggested that FOE5043-induced reductions in serum thyroxine (T₄) levels weremediated via an extrathyroidal site of action. The possibilitythat the alterations in circulating T₄ levels were due to chemicalinduction of hepatic thyroid hormone metabolism was investigated.Treatment with FOE 5043 at a rate of 1000 ppm as a dietary admixturewas found to significantly increase the clearance of [¹²⁵I]T₄from the serum, suggesting an enhanced excretion of the hormone.In the liver, the activity of hepatic uridine glucuronosyl transferase,a major pathway of thyroid hormone biotransformation in therat, increased in a statistically significant and dose-dependentmanner; conversely, hepatic 5'-monodeiodinase activity trendeddownward with dose. Bile flow as well as the hepatic uptakeand biliary excretion of [¹²⁵I]T₄ were increased following exposureto FOE 5043. Thyroidal function, as measured by the dischargeof iodide ion in response to perchlorate, and pituitary function,as measured by the capacity of the pituitary to secrete thyrotropinin response to an exogenous challenge by hypothalamic thyrotropinreleasing hormone, were both unchanged from the controlled response.These data suggest that the functional status of the thyroidand pituitary glands has not been altered by treatment withFOE 5043 and that reductions in circulating levels of T₄ arebeing mediated indirectly through an increase in the biotransformationand excretion of thyroid hormone in the liver.