RT Journal Article
SR Electronic
T1 Mechanisms by Which Inducers of Drug Metabolizing Enzymes Alter Thyroid Hormones in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-MR-2021-000498
DO 10.1124/dmd.121.000498
A1 Nichole R Vansell
YR 2022
UL http://dmd.aspetjournals.org/content/early/2022/01/19/dmd.121.000498.abstract
AB Increased disposition of thyroid hormones is a way that xenobiotics may alter thyroid homeostasis and in rats, produce thyroid follicular adenoma/carcinoma. This capacity is historically attributed to induction of T4 glucuronidation by UGT enzymes, and cytochrome P450 induction is often a surrogate. However, gaps exist in correlating the effectiveness of certain chemical inducers at increasing T4 glucuronidation with decreases in systemic T4 and resulting increases in TSH. With the identification of other key inducible drug processing genes and proteins involved in hepatic disposition of thyroid hormones, including uptake (eg, Oatps) and efflux (eg, Mrps) transporters, data exist that support transporters as additional targets sites of induction. These data are reviewed herein and indicate an increase in hepatic uptake of thyroid hormones, as well as increased biliary excretion of iodothyronine conjugates, represent critical activities that differentiate inducer effectiveness in disrupting thyroid hormones in rats. Increased membrane transport of thyroid hormones, likely in conjunction with induced glucuronidation of thyroid hormone (T3 more relevant than T4), provide a better indication of thyroid disrupting potential than consideration of UGT induction alone. Because coordinate regulation of these targets is inconsistent among inducers belonging to various classes and among species, and there are disparities between in vitro assays and in vivo responses, further work is required to identify specific and relevant inducible thyroid hormone uptake transporters. Data from Mrp2-null animals has contributed key information, yet the contributions of efflux transport (canalicular and basolateral) to the mechanism of individual, effective inducers also requires further study. Significance Statement Key advances in understanding the target sites for altered disposition of thyroid hormones have occurred in the last 2 decades to better inform potential sites of action of inducing chemicals. Ultimately, the knowledge of inducible thyroid hormone transport into and out of liver, beyond induction of glucuronidation, should be considered and applied to screening and risk assessment paradigms when assessing an inducer’s potential to alter thyroid homeostasis in nonclinical species and humans.