UDP-glucuronosyltransferase inducers reduce thyroid hormone levels in rats by an extrathyroidal mechanism

Abstract

As many microsomal enzyme inducers have been shown to reduce thyroid hormone levels, this study was conducted to determine if this reduction is produced by directly blocking the synthesis of thyroid hormones, or by indirectly increasing the biotransformation and deactivation of thyroxine (T₄) by microsomal enzymes. Surgically thyroidectomized male rats received thyroid hormone replacement therapy by implanted osmotic minipumps, resulting in T₄ and T₃ serum levels that were similar to those observed in euthyroid controls. Three days after minipump implantation (Day 0), rats were fed diets containing four UDP-glucuronosyltransferase (UDP-GT) inducers: phenobarbital (PB), 3-methylcholanthrene (3MC), pregnenolone-16α-carbonitrile (PCN), or polychlorinated biphenyls (PCB) for 10 days. PB, 3MC, and PCN reduced total (Days 3–10) and free (Days 7–10) T₄ serum concentrations 30–50%, whereas PCB produced a 70–75% reduction in total and free serum T₄ (Days 3–10). Treatment with PB, PCN, and PCB decreased levels of total T₃ (Days 7–10). UDP-GT activity toward T₄ was increased by PB, 3MC, PCN, and PCB 270, 400, 570, and 660%, respectively, and was found to correlate with serum T₄ levels (total and free). These results demonstrate that reduction of thyroid hormone levels by microsomal enzyme inducers is produced in part by an extrathyroidal mechanism, quite possibly an increase in T₄ glucuronidation.