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Department of Obstetrics-Gynecology, Winthrop University Hospital, Mineola, NY 11501
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGeneral MechanismsAttenuation of tissue and...Future directionsREFERENCES |
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KEY WORDS: • zinc • antioxidant • free radicals • oxidants • trace metals
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGeneral MechanismsAttenuation of tissue and...Future directionsREFERENCES |
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). A free radical is
any species that contains one or more unpaired electrons (Pryor 1966
). It will become apparent from this review that zinc does
not truly fit into either of these categories. Zinc has never been
shown to interact directly with an oxidant species but rather prefers
to exert its effects in an indirect manner. From a historical
perspective, perhaps the earliest example of zinc as an antioxidant is
its use in metallurgy. Zinc has been used for at least the past
100 y to galvanize iron or steel nails. In this process, the nail
is coated either electrically or through hot-dipping with zinc,
thus retarding air oxidation or rust formation. The past 20 y has
seen the generation of a large amount of information on the potential
role of this metal as a cellular antioxidant. Along with this
information has come the inevitable explosion of commercial products
seeking to take advantage of the often-anecdotal reports of
beneficial effects of zinc ingestion. Here, I attempt to present
information that will help to explain the antioxidant properties of
zinc and support the rationale use of zinc as a pharmacologic agent
under certain controlled clinical situations. |
General Mechanisms |
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TOPABSTRACTINTRODUCTIONGeneral MechanismsAttenuation of tissue and...Future directionsREFERENCES |
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), although the
biochemical basis of many of these effects are not clear. The acute
effects are generally thought to involve two mechanisms: protection of
protein sulfhydryls or reduction in the formation of
·OH from
H2O2 through the antagonism
of redox-active transition metals, such as iron and copper. What
follows is a discussion of the more recent literature that supports
these general mechanisms. The acute antioxidant effects of zinc and the
effects of zinc deficiency are described in detail. Chronic effects.
The effect of the chronic administration of zinc is the clearest
example of what is meant by an indirect effect. Virtually all of the
beneficial effects of long-term administration of zinc can be
linked to the induction of some other substance that serves as the
ultimate antioxidant. In this regard, the most studied effectors are
the metallothioneins. The metallothioneins are a group of
low-molecular-weight (6000–7000 kDa) metal-binding proteins
containing 60–68 amino acid residues, of which 25–30% are cysteine.
They contain no aromatic amino acids or disulfide bonds and can bind
5–7 g zinc (mol/protein) (Bernhard et al. 1987
,
Kagi and Hunziker 1989
, Kagi and Kojima 1987
). Numerous studies have demonstrated that the chronic
administration of zinc induces metallothionein in different organs such
as the liver (McCormick et al. 1981
), kidney
(Swerdel and Cousins 1982
) and intestine (Menard et al. 1981
). The metallothioneins have been shown to have
antioxidant effects under a variety of conditions, including radiation
exposure (Matsubara 1987
), toxicity from anticancer
drugs such as doxorubicin (Satoh et al. 1988
, Yin et al. 1998
) and others (Lazo and Pitt 1995
,
Lazo et al. 1998
), ethanol toxicity (Harris 1990
) and oxidatively mediated mutagenesis (Rossman and Goncharova 1998
). This list is by no means complete. Recent
studies have hypothesized that the metallothioneins are a link between
cellular zinc and the redox state of the cell. Under conditions of high
oxidative stress, changes in the cellular redox state result in release
of zinc from metallothionein as a result of sulfide/disulfide exchange
(Jiang et al. 1998a
, 1998b
, Maret 1994
, 1995
). The topic of metallothioneins and
zinc is discussed in detail in a subsequent review in this series.
Effects of chronic deprivation.
Numerous investigators have used chronic deprivation studies in
an attempt to answer the question of whether zinc has a physiological
role as an antioxidant. In general, long-term deprivation of zinc
renders an organism more susceptible to injury induced by a variety of
oxidative stresses. Interpretation of these studies can be difficult
because of the confounding problem of caloric reduction associated with
zinc deprivation. It is essential that a pair-fed control group be
included to differentiate between the specific effects of zinc
deprivation and caloric malnutrition. By and large the best evidence
for an increased susceptibility to oxidative injury comes from studies
in zinc-deprived animals; these studies have demonstrated either
increased free radical production or enhanced injury from exposure to
an oxidative stress. Because this topic has recently been extensively
reviewed, I opted to present this material in tabular form (Table 1
).
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Acute effects.
The acute antioxidant effects of zinc are generally manifested in the presence of a demonstrable short-term increase in levels of this metal. Basically two mechanisms have been described: sulfhydryl stabilization and reduction in the formation of ·OH from H2O2 and O2- through the antagonism of redox-active transition metals.
Sulfhydryl stabilization.
One of the acute effects of zinc is an apparent stabilization of
sulfhydryls, i.e., zinc protects certain enzyme sulfhydryls from
oxidation. The enzyme that has been most extensively studied is
-aminolevulinate dehydratase (EC 4.2.1.24), which catalyzes the
formation of the pyrrole porphobilinogen from two molecules of
-aminolevulinic acid. In humans, this enzyme exists as a
homo-octamer of identical subunits, each with a molecular
mass of 
31,000–35,000 kDa (Anderson and Desnick 1979
). -Aminolevulinate dehydratase are sulfhydryl
dependent, and there is a strong correlation between thiol oxidation
state and enzyme activity (Gibbs et al. 1985
,
Seehra et al. 1981
). Detailed studies have shown that 8
mol of zinc is bound per 1 mol of octamer and that the amount of bound
zinc closely correlates with enzyme activity. Zinc protects
-aminolevulinate dehydratase from oxygen inactivation, preventing
enzyme thiol oxidation and disulfide formation, whereas the
removal of zinc increases sulfhydryl reactivity and results in the loss
of enzyme activity. The protective effect of zinc was suggested to be
due to maintenance of an essential sulfhydryl group (group I) secondary
to decreased reactivity (Gibbs et al. 1985
).
Gibbs et al. (1985
) suggested several possibilities to
account for the stabilization of sulfhydryl groups: (1)
direct binding of zinc to the sulfhydryl; (2) binding to
some other protein site in close proximity to the sulfhydryl group,
resulting in steric hindrance; or (3) binding to some other
site on the protein, resulting in a conformational change, with the net
result of either of these processes being a reduction in sulfhydryl
group I reactivity (Fig. 1
). There are numerous other examples of thiol-dependent enzymes and
proteins containing thiol groups protected by zinc (Table 2
) (last reviewed in Bray and Bettger 1990
). Although in
general, these mechanisms can be applied to any protein or peptide
containing a sulfhydryl group, not all zinc-binding sulfhydryl
groups can be protected from oxidation; an important example is
zinc-metallothionein, in which sulfhydryl oxidation results in loss
of the metal (Fliss and Menard 1992
, Maret 1994
).
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Zinc has been shown in numerous systems to antagonize the catalytic properties of the redox-active transition metals iron and copper with respect to their abilities to promote formation of ·OH from H2O2 and superoxide. However, before presenting these studies, I would be remiss not to provide a basic review of the chemistry of the redox-active transition metals and how the formation of ·OH can promote various oxidative phenomena.
Redox-active transition metals as catalysts.
Several redox-active metals, including iron and copper
(Ambrosio et al. 1987
, Angel et al. 1986a
, 1986b
, Fuller et al. 1987
,
Holt et al. 1986
), and possibly nickel
(Torreilles and Guérin 1990
) and cobalt
(Moorhouse et al. 1985
), have been demonstrated to
catalyze formation of ·OH and other radicals.
There is a well known requirement for trace amounts of iron or copper
to catalyze formation of ·OH from
H2O2 and
O2- (Chvapil et al. 1973
,
Czapski et al. 1984
, Haber and Weiss 1934
, Kohen and Chevion, 1985
) through Fenton
chemistry according to the following reactions.
 | (1) |
 | (2) |
 | (3) |
 | (4) |
 | (5) |
 | (6) |
Reaction 2 is commonly known as the Haber-Weiss reaction and
is relatively slow. It has been suggested (Haber and Weiss 1934
) that trace amounts of soluble iron or copper in the
presence of reducing agents (AH2), such as
ascorbate, can catalyze the formation of hydroxyl radical from
superoxide via the metal-catalyzed Haber-Weiss reaction (Fenton
reaction (reaction 6).
Site-specific formation of radicals.
Transition metals, like iron and copper, tend to undergo hydrolytic
polymerization and precipitation in aqueous media at neutral pH
(Spiro et al. 1967
). It has been inferred that these
metals can remain in solution in physiological media only by
association with some high- or low-molecular-weight cellular
components, such as nucleotides, peptides, polypeptides, proteins or
DNA (Chevion 1988
, Chvapil et al. 1973
,
Czapski et al. 1984
). Intracellular free iron is more
likely to associate with low-molecular-weight ligands, such as
nucleotides, citrate, glycine and glucose (Halliwell and Gutteridge 1990
), whereas copper is more likely to associate
with macromolecular structures, such as DNA, carbohydrates, enzymes,
peptides and proteins (Bhat and Hadi 1994
, Creeth et al. 1983
, Gutteridge and Halliwell 1982
,
Uchida and Kawakishi 1990
). Once complexed at one of
these sites, movement of the metal is hindered, and the association
site can now serve as a locus for repetitive free radical formation
through repeated redox cycling of the metal. This has become known as
"site-specific" formation of radicals. Because the metal is fixed
in one place, any ·OH formed, by virtue of its
high reactivity, would attack adjacent structures, resulting in severe
localized damage. An excellent review on the subject of site
specificity can be found in Chevion (1988
).
Redox-active metals and tissue oxidative injury.
There is substantial evidence that metal-catalyzed formation of
·OH can initiate destructive processes.
Numerous studies have demonstrated that both copper and iron play a
critical role in the initiation and propagation of lipid peroxidation
(Fig. 2
). Metal-catalyzed formation of ·OH can
result in the abstraction of a hydrogen from an unsaturated fatty acid
leading to lipid radical formation. This can initiate a propagative
cascade of cyclical reactions, leading eventually to the repetitive
formation of short-chain alkanes and lipid acid aldehydes,
resulting in the destruction of lipid bilayers (Kappus 1985
). Another possible site of attack can include proteins.
The process of protein oxidation is initiated by the binding of a
reduced redox-active transition metal to an enzyme to form a
coordination complex that can then react with
H2O2 to form
·OH (Fig. 3
) (Fucci et al. 1983
, Oliver et al. 1990
,
Rivett 1985
, Stadtman 1990
,
Starke-Reed and Oliver 1989
). The hydroxy radical can
then abstract a hydrogen from the amino-bearing carbon, leading to
the formation of a carbon-centered protein radical that undergoes a
series of reactions, resulting in hydrolysis of the amino group and the
formation of an aldehyde or a protein carbonyl. Once the amino group is
hydrolyzed, the metal-binding site is disrupted, leading to
dissociation of the metal. Because the oxidative modifications occur
around the metal-binding site, the process of protein oxidation is
clearly an example of site-specific reaction. An excellent review
on the process of protein oxidation can be found in Stadtman (1990
).
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The basic assumption of the theory of site specificity is that the pool
of redox-active transition metals is associated with some cellular
component, thus establishing a site for the repetitive formation of
·OH. Accordingly, two potential processes that
would antagonize the formation of ·OH or
possibly shift the site of formation elsewhere to one less critical can
be theorized. The first of these processes would be to simply remove or
"pull" the metal off of its binding site through the use of high
affinity chelators. The other potential means would be to force, or
"push," the metal off of its binding site through the use of some
chemically similar, yet redox-inactive agent. The net result would
be to displace the metal into the cytosolic compartment, where it can
undergo hydrolytic polymerization and precipitation as unreactive
polynuclear structures (Eguchi and Saltman 1984
,
Spiro et al. 1967
), or possibly redistribute it to some
other less critical site, thus shifting the site of formation of
·OH (Fig. 4
). By virtue of similarities in coordination chemistry (Cotton and Wilkinson 1972
), it has been proposed that zinc can compete
with copper or iron for certain types of binding sites. This antagonism
has been most clearly demonstrated in several heme proteins where zinc
can effectively compete for Cu+2
site-specific binding (Hegetschweiler et al. 1987
,
Reid et al. 1987
).
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Perhaps the earliest report of metal antagonism in a chemical system
was a study demonstrating decreases in spin-trapped
·OH from iron and cysteine in the presence of
zinc, suggesting that competition between the two metals for the thiol
amino acid interfered with transfer of electrons to
O2 (Searle and Tomasi 1982
). In a
biochemical system, the earliest report was the observation that zinc
antagonized iron-mediated, xanthine/xanthine oxidase–induced
peroxidation of erythrocyte membranes (Girotti et al. 1985
). Since then, the antagonism has been characterized and
shown to be competitive in nature. In a rather elegant study,
Korbashi et al. (1989
) demonstrated that
zinc-nitrilotriacetate competitively antagonized
copper-nitrilotriacetate–mediated killing of Escherichia
coli by paraquat. There have been several other studies
demonstrating similar phenomenon; these are summarized in Table 3
. It was these earlier studies that provided the rationale for
subsequent studies that examined the ability of zinc to attenuate
cellular injury that might have a component of site-specific
oxidative injury.
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Attenuation of tissue and organ oxidative injury by acute administration of zinc |
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TOPABSTRACTINTRODUCTIONGeneral MechanismsAttenuation of tissue and...Future directionsREFERENCES |
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, Singal et al. 1982
). In vitro and in vivo studies demonstrated that zinc has
an inhibitory effect on isoproteronol-induced cardiac oxidative
injury (Persoon-Rothert et al. 1989
, Singal et al. 1982
). Since then, we have published a series of studies
describing the cardioprotective effects of zinc-bishistidinate in
several in vitro and in vivo models of cardiac ischemic injury
(Table 4
). There is substantial evidence documenting the presence of
various reactive oxygen intermediates in tissue, blood or perfusates
from postischemic organs (Arroyo et al. 1987
,
Bolli et al. 1988
, 1989
, Das et al. 1991
, Liu et al. 1990
, Onodera and Ashraf 1991
, Powell and Hall 1990
). This topic
has been the subject of many extensive reviews and is not discussed
here (Bulkley 1983
, Lucchesi and Mullane 1986
, Parks et al. 1983
, Powell 1994
, Powell and Tortolani 1992
, Sampson and Lucchesi 1987
). Our studies were among the first to
demonstrate the potential usefulness of zinc to attenuate ischemic and
postischemic injury. Since then, there have been numerous studies
demonstrating this property in a variety of ischemic tissues
(Table 5
). What should be apparent from this list is that investigators have
tried different complexes of zinc, ranging from the simple chloride
salt (Matsushita et al. 1996
) to zinc complexed with
protoporphyrin (Kadoya et al. 1995
). Although there have
been claims that one complex is superior to another, unless one can
demonstrate an additional effect (chemical or therapeutic) of the
complexing agent, in all likelihood it plays little if any role in the
overall protective effect other than acting as a delivery vehicle. The
fact remains that the one component that is common to all of these
studies is the presence of the zinc. Whether any of these complexes
eventually find their way into clinical usage remains to be seen but
certainly should be the topic of additional studies.
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Virtually all of the evidence demonstrating that the attenuation of
ischemic injury by zinc involves the inhibition of transition
metal–mediated site-specific oxidative injury is derived from
studies by our group. Our initial study examining the potential
mechanism of zinc-mediated cardioprotection demonstrated decreased
postischemic formation of ·OH when micromolar
concentrations of zinc were included in the perfusate of an isolated
heart (Powell et al. 1994
). As part of this study,
prolonged perfusion of isolated hearts with buffer containing zinc was
shown to significantly decrease cardiac copper content. More recent
studies (Powell et al. 1999
) in the isolated perfused
heart model have demonstrated that perfusion with zinc results in a
significant increase in the excretion of copper from the heart, thus
accounting for the decrease in myocardial tissue copper. The
involvement of site-directed phenomena in this process can be
inferred by the observation that zinc also decreased protein oxidation
in these ischemic hearts (Powell et al. 1999
). Although
hesitant to imply that the complex that we use is different from all
others that have been examined, the bishistidinate complex does have
some unique chemical properties. With respect to copper, the formation
constant of the histidinate complex of zinc is lower than that of the
histidinate complex of copper (12.88 versus 18.33, respectively)
(Ashmead et al. 1985
). This makes it possible for a
ligand exchange reaction to occur at the tissue-specific site in
which zinc exchanges with loosely bound copper, which then complexes
with histidine, essentially a "push-pull" phenomenon. The displaced
copper can then be washed out of the cell, reducing the availability of
the metal to participate in ·OH formation. The
occurrence of this process is in fact suggested by the presence of
increased excretion of copper from isolated hearts in the presence of
zinc. The observation that improvements in postischemic function are
associated with decreases in ·OH and
alterations in cardiac copper content provides a reasonable basis for
the theory that zinc is cardioprotective as a result of inhibition of
transition metal–mediated oxidative stress.
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Future directions |
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TOPABSTRACTINTRODUCTIONGeneral MechanismsAttenuation of tissue and...Future directionsREFERENCES |
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and Goldberg 1992
). It has been proposed that one pathway to cellular injury
and destruction is overactivation of these proteolytic systems. Thus,
the usefulness of any substance that can interfere with the initiating
steps in this process becomes clear and is worthy of further study. In
light of recent studies linking proteasome activation to apoptosis
mediated by caspases (for a review, see Thornberry and Lazebnik 1998
), research into the ability of zinc to inhibit these
processes deserves more attention, particularly since zinc has been
shown to be an antiapoptotic agent (for a review, see Zalewski et al. 1991
). Only by understanding the basic mechanisms by
which zinc can exert its antioxidant properties will we be able to
devise rational uses for this metal as an intervention not only in
ischemic damage but also in other forms of oxidative injury.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by National Institutes of Health Grant HL45534 and a grant from the Heart Council of Long Island,
Inc.
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TOPABSTRACTINTRODUCTIONGeneral MechanismsAttenuation of tissue and...Future directionsREFERENCES |
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