Chapter 3
Thermodynamics of Free Radical Reactions
and the Redox Environment of a Cell
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Klaudia Jomovaa and Marian Valko*,a,b
aDepartment
of Chemistry, Faculty of Natural Sciences,
Constantine The Philosopher University, SK-949 74 Nitra, Slovakia
bFaculty of Chemical and Food Technology, Slovak Technical University,
SK-812 37 Bratislava, Slovakia
*E-mail: [email protected]. Fax: +421-2-524 93 198.
This contribution reports on the thermodynamics of free radical
reactions and the maintenance of cell redox homeostasis.
Attention is focused on the definition of the half-cell reduction
potential and the reducing capacity of the antioxidant couples,
the cellular defence system substantiated by the thioredoxin,
NADP(H), ascorbic acid, and thiol-containing molecules
including glutathione (GSH), cysteine and protein thiols.
Triggering of the signalling processes in the cell require
the action of the electrochemical potential gradients of the
corresponding redox pairs. Experimental quantification of
electrochemical potential gradients of the corresponding redox
pairs is briefly discussed.
Introduction
Maintenance of a stable redox homeostasis plays a key role in the proper
functioning of cellular processes (1). Oxidative stress results from altered
redox homeostasis and has been linked with the development of many diseases
including, cardiovascular disease, diabetes, neurodegenerative disorders, cancer
and has also been implicated as an important factor in cell growth regulation
and ageing (2). Organisms have evolved a complex defence system based on
mechanisms comprised of non-enzymatic (low-molecular weight) and enzymatic
antioxidants.
© 2011 American Chemical Society
In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
The cellular defence system includes redox buffers such as the thioredoxin,
NAD(P)H, ascorbic acid, and thiol-containing molecules including glutathione
(GSH), cysteine and protein thiols (3). The reducing cellular environment creates
the electrochemical gradient necessary for electron transfer in oxidation-reduction
reactions occurring in biological systems. The aim of this contribution is to give
a brief overview of the thermodynamics of free radical reactions and the basic
principles and importance of the maintenance of the redox environment in the cell.
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Thermodynamics of Free Radical Reactions
A reductant, or reducing agent, is a substance that loses electrons and causes
another species to be reduced. Conversely, an oxidant, or oxidising agent, is
a substance that gains electrons and causes another species to be oxidised (4).
Oxidation (oxidation reaction) is a process in which a substance loses electrons
and reduction (reduction reaction) is a process in which a substance gains
electrons (5). Oxidation and reduction reactions are called redox reactions.
Redox reactions represent one of the most common and most important chemical
reactions occurring in biological systems. In the biochemistry of free radical
reactions we use more frequently the terms antioxidant and pro-oxidant, than
the terms reductant and oxidant, respectively (6). The thermodynamic principles
represent the basis for the prediction of the direction of chemical reactions
and thermodynamic quantities can conveniently be used to predict a hierarchy
for free radical reactions. Free radicals are species covering a wide range of
properties, ranging from those capable of strong oxidation to those capable of
strong reduction. One of the most important thermodynamic quantities suitable
for the characterization of the course of free radical reactions is the half-cell
reduction potential. For example, the one-electron reduction of a compound “A”
is related to the half-cell reduction potential of the couple (7):
The half-cell reduction potentials for many substances can be determined
by a variety of electrochemical techniques (8). Table 1 summarizes the values
of half-field reduction potentials of various species. They are listed from highly
oxidising (at the top of Table 1) to highly reducing (at the bottom of Table 1).
Oxidised species can accept electrons (hydrogens) from any reduced species
occurring below it in Table 1, or, conversely, reduced species are able to donate
electrons (hydrogens) to any oxidised species above it in Table 1.
The life time of free radicals is usually very short and therefore it is difficult
to maintain the thermodynamically reversible equilibrium at the surface of the
electrode in order to determine the exact values of half-cell potentials (10).
Therefore, a reliable estimate of half-cell potentials requires application of
fast kinetic methods (11). Table 1 summarises half-cell reduction potentials of
selected couples.
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Table 1. Half-cell reduction potentials of selected couples (pH = 7)
Eθ/mV (25°C)
Redox couples
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•OH,
H+/H2O
+2310
•OOH,
H+/H2O2
+1060
•OOR,
H+/ROOH
+770-1440
O2•–, 2H+/H2O2
+940
α-TO•, H+(Vit. E radical)/ α-TOH (Vit. E)
+500
H2O2, H+/H2O, •OH
+320
Asc•–,H+ (Ascorbyl rad.)/AscH– (Ascorbate)
+282
GSSG/2GSH
248
Redox reactions can generally be described by the set of equations:
An example of a simple type of redox reaction is:
This reaction consists of two half reactions:
In this case ferric ions are reduced from the +3 to the +2 oxidation state and
cupric ions are oxidised from +1 to +2 oxidation state. In oxidations and reductions
occurring in biological systems the electrons are often carried by protons and
therefore reactions are pH-dependent, since the concentration of H+ can itself
change the half-cell potentials of the redox couples (12).
The reaction Gibbs energy change of any reaction also involving a redox
reaction is given by the following equations (12):
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where ΔrGθ is the standard reaction Gibbs energy, R is the gas constant (8.314
Jmol-1 K-1), T is the thermodynamic temperature (K). Since ΔrG = -zFE we may
write:
This equation is called the Nernst equation and provides the electrical potential
which can be obtained from an oxidation-reduction reaction. Eθ is the standard
reduction potential defined as the potential of a couple at unit activity (ln1 = 0). F
is the Faraday constant = 96494 C/mol, and z is the number of electrons involved
in the process. At equilibrium ΔrG = 0, thus eqn. 8 simplifies to:
where K is the equilibrium constant of the reaction. For a general chemical
reaction (for example: aA + bB ↔ cC + dD), the equilibrium constant is defined
by the equation: K = (aAa.aBb)/(aCc.aDd) where aij is the dimensionless quantity
called activity, where subscript i refers to chemical species and superscript j
refers to stoichiometric coefficients a, b, c and d. They show up as powers of the
corresponding reactants and products.
For a spontaneous process, the change in the Gibbs free energy must be
negative (ΔrG < 0), thus from the equation (10) it follows that E must be positive
(E > 0) (13).
For any two redox pairs the overall redox potential is called the electromotive
force (ΔE) and is calculated according to the following equation:
The Nernst equation (9) using temperature at t = 25°C (298.15 K) and 2.303
as the conversion factor for the decadic logarithm can be rewritten
Thus from the eqn. (12) one may determine the electrochemical potential
between two redox couples.
As an example of these equations we refer here to a very important reaction
which takes place in biological systems, namely the regeneration of vitamin
E by vitamin C (14). Based on the half-cell reduction potential values of the
α-tocopheryl radical (α-T-O•)/α-tocopherol (α-T-OH, vitamin E) couple and an
ascorbate radical (Asc•−)/ascorbate monoanion (AscH−, vitamin C) couple it
is clear that the ascorbate monoanion can react with the tocopheryl radical to
regenerate vitamin E (15):
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ΔE is defined as the difference in the half-cell reduction potentials of the two
couples:
where E2 is the reduction potential for the half-cell reaction of the species that is
reduced (α-T-OH/α-T-O•) and E1 is the reduction potential for the half-cell reaction
of the species that is oxidized (AscH−/Asc•−). Thus the electromotive force ΔE for
this redox couple (ΔE = E2 – E1 = 0.5 – 0.282 = 0.218 V; see Table 1) is positive and
consequently the position of the equilibrium can be calculated. As the reduction
potential of the E1 couple is more negative than that of the E2 couple, ΔE becomes a
positive number and ΔG is negative. Hence the equilibrium constant K is positive
and so the equilibrium goes to the right-hand side. Thus vitamin C can react with
the vitamin E radical and regenerate it.
When discussing reactions occurring in living systems, the thermodynamic
principles are not the only ones which should be considered. The issue of
kinetics of the process also play an important role, because any reaction that is
thermodynamically possible may not be kinetically feasible; in other words the
reaction is too slow to be biologically important (16).
Since biological systems are not in equilibrium (equilibrium = death), the
conditions of reversibility cannot be fulfilled and therefore the redox potential
cannot be determined according to its theoretical definition. More suitable is the
term redox state which is applied not only to describe the state of a particular redox
couple, but also, in the broader sense, to describe the redox environment of a cell
(6).
Many redox reactions occurring in living systems are represented by
two-electron processes, avoiding thus the formation of free radicals (17).
Similarly to one-electron reactions described above, there is a thermodynamic
hierarchy for the two-electron redox reactions (see Table 2). There are two
important redox couples (see below) significantly influencing the cellular redox
environment. These involve the glutathione system (GSSG/GSH) and the
thioredoxin system (TRX-SS/TRX-(SH)2) (17). A major source of electrons
for reductive biosynthesis including the glutathione and thioredoxin systems
is the nicotinamide adenine dinucleotide system (NAD+/NADH) (18). The
NAD(P)+/NAD(P)H system is described by the reaction
This reaction can be described by two steps
and overall reaction
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Table 2. Two-electron reduction potentials of selected couples at pH = 7
Eθ/mV (25°C)
Redox couples
Xanthine/hypoxanthine, H+
-371
Uric acid/xanthine, H+
-360
NAD+, H+/NADH
-316
NADP+, H+/NADPH
-315
GSSG, 2H+/2GSH
-240
TRX-SS, 2H+/TRX-(SH2)
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GRX-SS,
FAD,
-270 to -124 (mean value -240)
2H+/GRX-(SH2)
-218
2H+/FADH2
Pyruvate,
-219
2H+/Lactate
Dehydroascorbate,
H+/Ascorbate
Ubiquinone (CoQ),
2H+/ubihydroquinone
-183
+54
(CoQH2)
+84
O2, 2H+/H2O2
+300
H2O2, 2H+/2H2O
+1320
The value of the overall reaction (-316 mV) in which two-electrons are
exchanged, can be regarded as the average of the two one-electron reactions.
The half cell reduction potential described by the Nernst equation for the
overall reaction (NAD(P)+, H+/NAD(P)H couple) can be expressed as
Assuming the concentrations of NAD(P)H and NAD(P) to be 80μM and
0.8μM, respectively, the equation can be rewritten as (19)
The value of E is very negative and is in agreement with the idea that the
NAD(P)+/NAD(P)H system is a key player in maintaining the reducing cell
environment.
Now we describe the glutathione couple. The half reaction for the GSSG/
2GSH couple is
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and the Nernst equation is given by
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The ratio of reduced to oxidised glutathione is approximately 100:1, thus
assuming the concentrations of reduced glutathione and oxidised glutathione are
5 mM and 50 μM, respectively, the Nernst equation is (20)
The thioredoxin are a family of di-cysteine proteins participating in the
electron transfer reactions. The half-reaction for this redox pair can be expressed
according to the reaction (see Figure 1) (21)
Figure 1. Formation of TRX-(SH)2 from TRX-SS.
In this reaction one molecule of TRX-SS forms one molecule of TRX-(SH)2
and the Nernst equation can be expressed in the following form
Redox Environment of the Cell
Schafer and Buettner recently suggested that the redox state of a redox couple
(for example α-T-OH/α-T-O• or AscH−/ Asc•−) is defined by the half-cell reduction
potential and the reducing capacity of that couple (1). The redox state of all redox
couples contributes to the redox environment of the cell.
The redox state of a biological system is given by the “total number of
electrons” and is kept within a narrow range under normal conditions – in analogy
according to which a biological system regulates its pH. Oxidative stress results
in alterations of the redox state. A 30 mV change in the redox state means a
10-fold change in the ratio between reductant and oxidant (1).
Mitochondria use more than 90% of the cellular oxygen consumption.
The mitochondrial electron transport chain is represented by a series of redox
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reactions in which four electrons are transferred to oxygen which is subsequently
reduced to water. However, in the course of the electron transport chain a
small amount of dioxygen is reduced to superoxide by single electrons that leak
(from 0.25 to 2%) from the electron transport chain (22). A small proportion of
moving electrons that are not used for the energy production but are shunted to
oxygen to form superoxide radical anions (and hydrogen peroxide) represents
initiating species of redox cascades functioning in biological systems (23). Under
physiological conditions, the steady state levels of superoxide and hydrogen
peroxide molecules are very low. Hydrogen peroxide is an oxidant molecule
participating in two-electron oxidation, typical for altering the redox equilibrium
of thiol molecules activating thus the signalling pathways responsible for cell
differentiation or alternatively at high flux cell apoptosis and necrosis (24).
Glutathione is the master antioxidant and smallest intracellular non-protein
thiol molecule in the cells. Glutathione together with thioredoxin, which is
represented by a group of small redox proteins are both responsible for the
maintenance of the cellular redox state (25).
The thioredoxins are more specific than the glutathione system (26).
Thioredoxins are known to react with approximately twenty biomolecules that
are involved in various regulatory and catalytic processes. The thioredoxins are
more specific than the glutathione system. Thioredoxin functioning interferes
with the transcription factors such as NF-kappaB, AP-1 and the glucocorticoid
receptor. Thioredoxins are also known to regulate stress signalling pathways,
such as stress kinases ASK1 (27).
Glutathione is the major soluble antioxidant in these cell compartments and
occurs in the cytosol (1–10 mM), nuclei (3–12 mM), and mitochondria (5–10 mM).
Since GSH is synthesized in the cytosol, its mitochondrial functioning requires
the mitochondrial electroneutral antiport carrier. The transport of GSH has been
documented by experiments in which externally added GSH is readily taken up by
mitochondria, despite the ~8mM GSH present in the mitochondrial matrix (28).
A higher concentration of glutathione in the cell is more protective to the cell and
requires a higher oxidation stimulus to change the redox cellular environment.
Thus when examining the redox-buffer capacity of the cell one should consider
the total concentration of GSH. Concentrations of GSH vary from cell to cell, for
example liver cells contain approximately 5 mM of GSH.
Glutathione action in the nucleus is substantiated by the maintenance of the
redox state of critical protein sulfhydryls that are necessary for the repair of DNA.
An oxidative environment leads to oxidation of protein sulfhydryls (protein-SH):
two electron oxidation yields sulfenic acids (protein-SOH) and one-electron
oxidation yields thiyl radicals (protein-S•) (see Figure 2) (29).
Glutathione accomplishes its protective role against deleterious effect of
reactive oxygen species (ROS) by the following mechanisms (30): (i) GSH is
involved in amino acid transport through the plasma membrane, (ii) GSH is a
direct scavenger of ROS including singlet oxygen, (iii) GSH regenerates various
antioxidants, including ascorbic acid and alpha-tocopherol from their radical
forms back to their active forms and (iv) GSH is a cofactor of various antioxidant
enzymes.
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Figure 2. Protection of protein sulfhydryl groups by GHS.
The attack of proteins by ROS and reactive nitrogen species (RNS) affects
practically all amino acid residues and polypeptide backbone (2). The attack of
free radicals to proteins may lead to the oxidation of the amino acids. Cysteine and
methionine residues of proteins are particularly susceptible to oxidation by ROS
(2, 22). The –SH (thiol or sulfhydryl) groups of cysteine aminoacids are the most
vulnerable aminoacids to reversible and irreversible oxidation. The accumulation
of oxidatively modified proteins plays an important role in the process of ageing.
A moderate oxidative environment confirmed by two-electron oxidation
may lead to the formation of reversible sulfenic acid derivatives of cysteine
(Protein-SOH, sulfenic acid) and via one electron oxidation to the thiyl radicals
(protein-S•) (31). These partially oxidised products react with a tripeptide
glutathione (present in the cytoplasm in millimolar concentration) and form
S-glutathiolated protein (protein-SSG). If the process of oxidation of protein
sulfhydryls is not interrupted by glutathione, further oxidation results in the
formation of irreversibly oxidised products such as sulfinic (protein-SO2H) and
sulfonic (protein-SO3H) acids (22, 31). Thus when oxidative stress exceeds
the potentially dangerous threshold, the process of S–glutathiolation triggers
protective mechanisms against irreversible and deleterious oxidation of sensitive
cysteine residues under conditions of oxidative stress.
The high abundance of reduced forms of both GSH and TRX is maintained
by the activity of GSH-reductase and TRX-reductase, respectively (32). Both of
these “redox buffering” thiol systems not only counteract intracellular oxidative
stress and act as antioxidants in the cell, but they are also involved in cell signalling
process (3, 33). In addition to GSH and TRX, there are other both hydrophylic and
lipophilic low molecular weight antioxidants, that when present at physiological
concentration, can significantly contribute to overall ROS scavenging activity.
Triggering of the signalling processes in the cell require the action of
the electrochemical potential gradients of the corresponding redox pairs.
Experimental quantification of these gradients is now only in the early stage of
development (34). The suitable systems in this respect are tumours characterized
by the pronounced heterogeneity in their redox environment and partial pressure
of oxygen, compared to healthy tissue.
Electron paramagnetic resonance (EPR) imaging is a suitable method for
monitoring the redox status modulated by oxidative stress in vivo (35). EPR
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spectroscopy, also referred to as Electron Spin Resonance (ESR) spectroscopy, is
a nondestructive sensitive analytical technique which can be used for studies of
species containing at least one unpaired electron (36). Such species are termed
paramagnetic. In the EPR experiment, the sample, containing paramagnetic
species with one or more unpaired electrons, is placed in a magnetic field,
which removes the degeneracy of the various spin states of the paramagnetic
particle. Transitions between the different spin states (alpha and beta) can then be
induced by irradiation at the appropriate microwave frequency. The record of the
absorption of the microwave radiation by the sample is the EPR spectrum. The
EPR spectrum is sensitive to the nature and physical and chemical environment
of the unpaired electrons and therefore it is very useful for the characterization of
paramagnetic centers. The EPR spectroscopy has found numerous applications
in chemistry, physics, biology and medicine. A very useful technique employed
for the detection and characterization of short-lived radical species is EPR spin
trapping (37). This technique is based on the application of a diamagnetic
molecule (spin trap) which preferentially interacts with a reactive free radical to
form a more stable spin adduct which can be detected by EPR technique. The
most useful radical trap for the detection of oxygen-centered free radicals is
5,5-dimethyl-1-pyrroline N-oxide (DMPO).
Low-frequency EPR and EPR-imaging techniques using nitroxide redox
probes are in particular suitable for the monitoring of the cell redox environment
status as well for the detection of the cellular hypoxic state that marks the
onset of tumoural angiogenesis. In EPR experiments on tumour tissues of
radiation-induced fibrosarcoma (RIF-1) tumour-bearing mice it has been
confirmed that there is significant heterogeneity of redox status in the tumour
tissue compared with normal tissue (38). EPR imaging has revealed that tumour
tissues contain 4-fold higher concentrations of GSH levels compared with
normal tissues. The significant heterogeneity of tumour cell redox status and the
possibility of the fine tuning of the redox status of cancer cells may open new
horizons in cancer therapy.
Acknowledgments
The authors appreciate funding by the Scientific Grant Agency of the
Slovak Republic (Projects VEGA #1/0856/11) and by the Slovak Research and
Development Agency of the Slovak Republic (Contract No.APVV-0202-10).
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