In vitro metabolism of thyroxine by rat and human hepatocytes

Abstract

1. The liver metabolizes thyroxine (T₄) through two major pathways: deiodination and conjugation. Following exposure to xenobiotics, T₄ conjugation increases through the induction of hepatic uridine diphosphate glucuronosyltransferase (UGT) in rodents; however, it is uncertain to what degree different species employ deiodination and conjugation in the metabolism of T₄. The objective of this study was to compare the metabolism of T₄ in untreated and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB 153)-treated primary sandwich-cultured hepatocytes from rat (SCRH) and human (SCHH).

2. Basal metabolite concentrations were 13 times higher in the medium of SCRH compared to SCHH. Metabolite distribution in the medium of SCRH versus SCHH was as follows: T₄G, (91.6 versus 5.3%); T₄S, (3.6 versus 4.4%) and T₃ + rT₃, (4.9 versus 90.3%). PCB 153 induced T₄G in the medium of SCRH and SCHH; however, T₄S and T₃ + rT₃ were changed but to a much lesser degree.

3. The results indicate that baseline T₄ glucuronidation is greater in SCRH compared to SCHH. These data also suggest that glucuronidation may be a more important pathway for T₄ metabolism in rats and deiodination may be a favored pathway in humans; however, with PCB 153 treatment these data support glucuronidation as a primary route of T₄ metabolism in both rat and humans.

• Deiodination
• glucuronidation
• PCB 153
• sulfation
• thyroid hormone
• T₄

Acknowledgements and disclaimer

The authors would like to thank Drs. Scott Auerbach, Michael Hughes, and Jane Ellen Simmons for critical review of the manuscript. This article is the work product of a group of employees of the NIEHS, National Institutes of Health (NIH) and the US Environmental Protection Agency, however, the statements contained herein do not necessarily represent the statements, opinions or conclusions of the NIEHS, NIH, USEPA, or the US Government. The content of this publication does not necessarily reflect the views or the policies of the Department of Health and Human Services or the USEPA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.