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

ifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide (FOE 5043) is a new acetanilide-type herbicide undergoing regulatory testing. Previous wo rk in this laboratory suggested that FOE 5043-induced reductions in se rum thyroxine (T-4) levels were mediated via an extrathyroidal site of action. The possibility that the alterations in circulating T-4 level s were due to chemical induction of hepatic thyroid hormone metabolism was investigated. Treatment with FOE 5043 at a rate of 1000 ppm as a dietary admixture was found to significantly increase the clearance of [I-125]T-4 from the serum, suggesting an enhanced excretion of the ho rmone. In the liver, the activity of hepatic uridine glucuronosyl tran sferase, a major pathway of thyroid hormone biotransformation in the r at, increased in a statistically significant and dose-dependent manner ; conversely, hepatic 5'-monodeiodinase activity trended downward with dose. Bile how as well as the hepatic uptake and biliary excretion of [I-125]T-4 were increased following exposure to FOE 5043. Thyroidal f unction, as measured by the discharge of iodide ion in response to per chlorate, and pituitary function, as measured by the capacity of the p ituitary to secrete thyrotropin in response to an exogenous challenge by hypothalamic thyrotropin releasing hormone, were both unchanged fro m the controlled response. These data suggest that the functional stat us of the thyroid and pituitary glands has not been altered by treatme nt with FOE 5043 and that reductions in circulating levels of T-4 are being mediated indirectly through an increase in the biotransformation and excretion of thyroid hormone in the liver. (C) 1996 Society of To xicology