Sulfur Amino Acid and Acetaminophen Effects on Extracellular Thiol/Disulfide Redox
By Yanci O. Mannery
Recent evidence demonstrates the importance of thiol/disulfide redox potential in
control of biological processes such as cell proliferation, differentiation, and apoptosis.
In human plasma, cysteine (Cys) and cystine (CySS) constitute the most abundant low
molecular weight thiol/disulfide couple, and the steady-state redox potential of this
couple, EhCySS, is one of the central physiologic systems controlling redox homeostasis.
In vivo studies show that plasma EhCySS becomes oxidized with aging, disease, and
lifestyle choices. The purpose of this dissertation was to study the effects of sulfur amino
acid (SAA) availability and acetaminophen (APAP) administration on extracellular
Cys/CySS redox potential (EhCySS) and potential mechanisms involved.
The first section of the dissertation used a human intestinal cell culture model to
investigate mechanisms for regulation of extracellular EhCySS. The basal surface more
rapidly adjusted EhCySS toward the physiologic value of -80 mV compared to the apical
following exposure to an oxidized condition. Experiments designed to test specific
mechanisms for regulation of EhCySS on the basal surface showed that redox regulation
required Na+ in the culture medium, suggesting a requirement for a transport system.
Transport inhibition experiments indicate that EhCySS on the basal surface is controlled
by y+L and x -
The second and third sections of the dissertation were designed to test whether a)
dietary SAA availability or acute acetaminophen administration regulate plasma EhCySS
and b) SAA insufficiency alters APAP metabolism in healthy adults. With adequate SAA
intake, APAP administration oxidized the plasma Cys/CySS redox potential (EhCySS).
However, APAP administration with 0% SAA did not cause further oxidation beyond
APAP or 0% SAA alone. While results show that therapeutic drug use can affect plasma
EhCySS, SAA limitation was not sufficient to cause a change in the pharmacokinetic
properties for disposition of APAP in humans.
Together, these studies show that Cys and CySS transport mechanisms are
important in the regulation of plasma redox potential in human gut epithelial cells and
that plasma EhCySS is dependent both upon SAA intake and exposure to acetaminophen.
Future studies are indicated to define relevant signaling pathways for redox regulation of
the Cys and GSH pools and the responses to dietary SAA availability during illnesses
when acetaminophen is administered.
Sulfur Amino Acid and Acetaminophen Effects on Extracellular
Yanci O. Mannery
B.S., Dillard University, 2002
Advisor: Dean P. Jones, Ph.D.
Advisor: Thomas R. Ziegler, M.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
in Molecular and Systems Pharmacology
Table of Contents
TABLE OF CONTENTS
CHAPTER 1: INTRODUCTION
Quantitative Definition of Redox Potential
Intracellular Redox Environment
Extracellular Redox Environment
Factors Affecting Extracellular Cys/CySS Redox
Sulfur Amino Acid Metabolism
Recommended Dietary Allowance for Sulfur Amino Acids
Sulfur Amino Acid Availability and Thiol/Disulfide Redox
Acetaminophen Pharmacokinetics and Metabolism
Chemical Detoxification and Sulfur Amino Acid Availability
Research Questions and Hypotheses
CHAPTER 2: CHARACTERIZATION OF APICAL and BASAL
THIOL/DISULFIDE REDOX REGULATION IN HUMAN COLONIC
Materials and Methods
About this Dissertation
|Committee Chair / Thesis Advisor|
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