In Vitro method development for studying comparative induction of UGTs using primary rat and human hepatocytes

The liver plays a key role in regulating the plasma concentrations of thyroid hormone (TH) and T4-glucuronidation is one of the major pathways influencing TH bio availability. Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are phase II enzymes found in the liver that are responsible for glucuronidation of metabolites to facilitate systemic elimination. Xenobiotics can interfere with TH homeostasis by decreasing circulating concentrations of TH through induction of thyroxine(T4) glucuronidation. This may lead to a compensatory increase in the secretion of thyroid-stimulating hormone, causing increased thyroid follicular cell hypertrophy, proliferation and ultimately follicular cell adenomas/carcinomas. The molecular initiating effect is the increased expression and activity of UGTs, particularly those involved in the glucuronidation of T4.An in vitro comparative UGT assay may be conducted to determine the human relevance of this mode of action (MOA).Data from animal toxicity studies shows that thyroid histopathological and weight effects are correlated with liver effects. Induction of UGT liver enzymes is commonly observed following exposure to exogenous substances. Many chemicals interact with CAR/PXR/AhR-nuclear receptors that modulate the expression of specific CYP (phase I) and UGT genes (phase II).Rats are exquisitely more sensitive to TH changes, and subsequent microscopic changes in thyroid, than humans; hence the “species differences”. This MOA therefore is not considered relevant to humans due to differences in TH clearance rate.