Sulfur Amino Acid and Acetaminophen Effects on Extracellular Thiol/Disulfide Redox Potentials Open Access
Mannery, Yanci Olivia (2010)
Published
Abstract
Abstract
Sulfur Amino Acid and Acetaminophen Effects on Extracellular
Thiol/Disulfide Redox
Potentials
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 -
c .
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
Thiol/Disulfide
Redox Potentials
By
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
2010
Table of Contents
TABLE OF CONTENTS
Page
CHAPTER 1: INTRODUCTION
1
1.1
Quantitative Definition of Redox Potential
2
1.2
Intracellular Redox Environment
4
1.3
Extracellular Redox Environment
5
1.4
Factors Affecting Extracellular Cys/CySS Redox
8
Homeostasis
1.5
Sulfur Amino Acid Metabolism
11
1.6
Recommended Dietary Allowance for Sulfur Amino Acids
13
1.7
Sulfur Amino Acid Availability and Thiol/Disulfide Redox
13
Homeostasis
1.8
Acetaminophen Pharmacokinetics and Metabolism
14
1.9
Chemical Detoxification and Sulfur Amino Acid Availability
16
1.10
Research Questions and Hypotheses
17
CHAPTER 2: CHARACTERIZATION OF APICAL and BASAL
THIOL/DISULFIDE REDOX REGULATION IN HUMAN COLONIC
EPITHELIAL CELLS
2.1
Abstract
35
2.2
Introduction
36
2.3
Materials and Methods
38
2.4
Results
41
2.5
Discussion
46
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