Effects of thyroid status and thyrostatic drugs on hepatic glucuronidation of iodothyronines and other substrates in rats - Induction of phenol UDP-glucuronyltransferase by methimazole

Glucuronidation of iodothyronines in rat liver is catalyzed by at least three UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT, and androsterone UGT. Bilirubin and phenol UGT activities are regulated by thyroid hormone, but the effect of thyroid status on hepatic glucuronidation of iodothyronines is unknown. We examined the effects of hypothyroidism induced by treatment of rats with propylthiouracil (PTU) or methimazole (MMI) or by thyroidectomy as well as the effects of T4-induced hyperthyroidism on the hepatic UGT activities for T4, T3, bilirubin, p-nitrophenol (PNP), and androsterone. Bilirubin UGT activity was increased in MMI- or PTU-induced hypothyroid and thyroidectomized rats, and decreased in hyperthyroid animals. T4 and, to a lesser extent, T3 UGT activities were increased in MMI- or PTU-induced hypothyroid rats, and T4 but not T3 glucuronidation also showed a significant increase in thyroidectomized rats. T4 but not T3 UGT activity was slightly decreased in hyperthyroid rats. While PNP UGT activity was decreased in thyroidectomized rats and increased in hyperthyroid animals, it was also markedly increased by MMI and slightly increased by PTU-induced hypothyroidism. In T4-substituted rats, MMI did not affect T4, T3, bilirubin and androsterone UGT activities but again strongly induced PNP UGT activity, indicating that this represented a direct induction of PNP UGT by the drug independent of its thyrostatic action. Androsterone UGT activity was hardly affected by thyroid status. Our results suggest a modest, negative control of the hepatic glucuronidation of thyroid hormone by thyroid status, which may be mediated by changes in bilirubin UGT activity. To our knowledge, this is the first report of the marked induction of a hepatic enzyme by MMI, which is not mediated by its thyroid hormone-lowering effect.