Mathematical Modeling of Thyroid Hormone Metabolism in the Human Liver Público

Abstract

Background: Thyroid hormones (THs) including T3 and T4 play an important role in human development and energy regulation. In the liver there are three major metabolic pathways of THs including deionization by deiodinases (DIO), sulfation by sulfotransferases (SULT), and glucuronidation by glucotransferase (UGT). Many of these enzymes can be induced or inhibited by thyroid disrupting chemicals (TDCs), leading to TH-associated adverse disease outcomes. However, the quantitative effects of these hepatic perturbations on TH metabolism are unknown.

Objective: (1) Collect literature information on the kinetic parameters of hepatic DIOs, SULTs and UGTs metabolizing THs in the human liver. (2) Develop a mathematical model of TH metabolism in the liver. (3) Use the mathematical model to investigate quantitatively how TDCs-induced changes of TH metabolic enzymes would alter hepatic TH levels and metabolic fluxes.

Methods: An ordinary differential equation (ODE)-based deterministic model of TH metabolism in the liver was developed in R. Steady-state concentrations of various species of THs, including T4, T3, reverse T3 (rT3), T2, and their sulfated and glucuronidated forms and the associated metabolic fluxes were calculated. Sensitivity analysis and dose-response simulations were conducted to measure the changes in THs and TH fluxes in response to changes in enzyme levels.

Results: Hepatic T4 and T3 levels are highly resistant to enzymatic perturbations, because the influx and efflux of T3 and T4 between the liver and plasma play a dominant role. In contrast, the flux from T4 to T3 and from T4 to rT3 are highly sensitive to DIO1. The flux from T4 to T4G is sensitive to UGT and the sensitivity is UGT1A9 > UGT1A1 > UGT1A3. The flux from T4 to T4S is sensitive to SULT and the sensitivity is SULT1A1 > SULT1E1. The model predicts that free T4 is about 0.04% of total T4 and free T3 about 0.5% of total T3 in the liver.

Conclusion: A mathematical model of TH metabolism in the liver can be an important tool in studying TH metabolism in the liver. It can provide new information and insights into the thyroid health risk of TDCs targeting liver enzymes.

Table of Contents

INTRODUCTION-------------------------------------------------------------------------------------------------------1

• Physiology of thyroid hormone-----------------------------------------------------------------------1

• Thyroid hormone metabolism in the liver----------------------------------------------------------1

o Deiodination------------------------------------------------------------------------------------1

▪ Type 1 Deiodinase (DIO1)---------------------------------------------------------2

▪ Type 2 Deiodinase (DIO2)---------------------------------------------------------2

▪ Type 3 Deiodinase (DIO3)---------------------------------------------------------3

o Sulfation-----------------------------------------------------------------------------------------3

o Glucuronidation--------------------------------------------------------------------------------3

• Thyroid disrupting chemicals in thyroid disease-------------------------------------------------4

o Polychlorinated Biphenyls (PCB)----------------------------------------------------------4

o 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-------------------------------------------5

o Halogenated Phenolic Contaminants (HOCs)------------------------------------------5

o Bisphenol-A (BPA)----------------------------------------------------------------------------5

• Role of mathematical modeling in studying TH metabolism and thyroid diseases------5

• Objective of this study----------------------------------------------------------------------------------6

METHODS---------------------------------------------------------------------------------------------------------------7

• ODEs of the mathematical model of TH metabolism in the liver----------------------------7

• Derivation of parameter values for hepatic TH metabolism----------------------------------12

o Hepatic TH Influx and Efflux---------------------------------------------------------------12

o Deiodination-----------------------------------------------------------------------------------12

▪ Initial Km values---------------------------------------------------------------------13

▪ Initial Vmax values-------------------------------------------------------------------13

o Glucuronidation------------------------------------------------------------------------------13

▪ Initial Km values---------------------------------------------------------------------14

▪ Initial Vmax values-------------------------------------------------------------------14

o Sulfation----------------------------------------------------------------------------------------15

▪ Initial Km and Vmax for SULT1A1-------------------------------------------------15

▪ Initial Km and Vmax for SULT1B1-------------------------------------------------15

▪ Initial Km and Vmax for SULT1E1-------------------------------------------------15

▪ Initial Km and Vmax for SULT2A1-------------------------------------------------16

▪ Further adjustments according to expression ratio-------------------------16

o Determination of free fraction of THs in the liver and fine tuning of enzymatic parameters------------------------------------------------------------------------------------16

• Sensitivity analysis------------------------------------------------------------------------------------18

• Simulation Software-----------------------------------------------------------------------------------18

RESULTS--------------------------------------------------------------------------------------------------------------19

• Steady-state Levels of THs and Fluxes-----------------------------------------------------------19

• Sensitivity analysis------------------------------------------------------------------------------------19

• Dose-response analysis-----------------------------------------------------------------------------19

DISCUSSION---------------------------------------------------------------------------------------------------------21

REFERENCE---------------------------------------------------------------------------------------------------------25

TABLES AND FIGURES-------------------------------------------------------------------------------------------27

About this Master's Thesis

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School	Rollins School of Public Health
Department	Environmental Health
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Toxicology
Palavra-chave	Thyroid Hormone Mathematical Modeling
Committee Chair / Thesis Advisor	Qiang, Zhang, Emory University

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