Ürik Asidin Antioksidan ve Pro-Oksidan Özellikleri ile İlgili Kavram ve Tartışmalarının Derlemesi
Ar?iv Kaynak Tarama Dergisi
Archives Medical Review Journal
Review of Concepts and Controversies of Uric Acid as Antioxidant and Pro-Oxidant ?rik Asidin Antioksidan ve Pro-Oksidan ?zellikleri ile ?lgili Kavram ve Tart??malar?n?n Derlemesi
Amar Nagesh Kumar 0
Pathiputhuru Aruna 0
Jupalle Nagaiah Naidu 0
Robby Kumar 1
Anuj Kumar Srivastava 2
0 Department of Biochemistry, Narayana Medical College , Nellore, Andhra Pradesh , India
1 Department of Biochemistry, SSR Medical College , Mauritius
2 Department of Surgery, SSR Medical College , Mauritius
Uric acid, the end product of purine catabolism in humans and is known for its crystal deposition at higher concentrations (>7 mg/dl) in gout. Less is known about its antioxidant property and the beneficial effects in various diseases. It is thought that high concentration of uric acid in humans is an evolutionary advantage and it is also hypothesized that high concentration of uric acid is to compensate the antioxidant capacity of ascorbic acid which is lost in humans during the course of evolution. In the extracelluar environment, uric acid can scavenge free radicals like hydroxyl radical, singlet oxygen and peroxynitrite radical therefore, it is considered as a powerful antioxidant. On the other hand uric acid depending upon the chemical milieu, changing its property and at times it acts as pro oxidant and is associated with the pathobiochemistry in developing various diseases like hypertension, cardio vascular diseases, ischemia reperfusion injury, diabetes mellitus, non alcoholic fatty liver disorders etc. In this review, we tried to summarize the evolutionary advantages of hyperuricaemia, effects of both antioxidant property and pro-oxidant nature of uric acid in various disease conditions.
?ZET ?rik asit; insanlarda p?rin metabolizmas?n?n son ?r?n?d?r; gutta kristallerinin yo?un olarak (>7
mg/dl) birikti?i bilinmektedir. ?nsanlarda, y?ksek konsantrasyonda ?rik asitin evrimsel bir avantaj
oldu?u d???n?lmektedir.Ayn? zamanda, insanlarda y?ksek ?rik asit konsantrasyonunun; evrim
s?recinde kaybolan askorbik asitin antioksidan kapasitesini telafi etti?i hipotezi ortaya at?lm??t?r. H?cre
d??? ortamda, ?rik asit; hidroksil, peroksinitrit ve tekil oksijen gibi serbest radikalleri
uzakla?t?rabilmektedir bu sebeple ?rik asit g??l? bir antioksidan olarak d???n?lmektedir. ?te yandan
kimyasal ortam?na ba?l? olarak de?i?en ?zelli?i ile ?rik asit, zaman zaman pro-oksidan gibi davran?r ve
hipertansiyon, kalp damar hastal?klar?, iskemi reperf?zyon hasar?, diyabet, ve alkols?z ya?l? karaci?er
bozukluklar? gibi ?e?itli hastal?klar?n patokimyas? ile ili?kilidir. Bu ?al??mam?zda, hiper?reseminin
evrimsel avantajlar?n? ve ?e?itli hastal?k ko?ullar?nda, ?rik asitin hem antioksidan ?zelli?inin hem de
pro-oksidan do?as?n?n etkilerini ?zetlemeye ?al??t?k.
Anahtar kelimeler: Hiper?resemi, antioksidan, pro-oksidan, paradoks, ?rik astin faydal? etkileri.
Uric acid (UA) is the end of purine catabolism and is excreted in urine of humans. It is a weak
organic acid with a PK of 5.75, and exists mainly as monosodium urate (MSU) at physiological
PH. In most mammals, uric acid is degraded further by the enzyme uricase. The pathway of
purine catabolism is shortest among humans and great apes, because about 5?20 million
years ago the activity of uricase gene was lost during hominoid evolution1 Therefore uric acid
is the final product in humans and great apes, which is excreted in urine, whereas in other
mammals the final enzymatic product of purine degradation is allantoin and is excreted in the
urine. As a consequence, humans and the great apes have to bear with higher uric acid levels
(>2 mg/dl) compared with most mammals (< 2mg/dl) and they are more prone to
hyperuricemia (>6.5 mg/dl).
Many researchers do not consider uric acid as an antioxidant. They forget about the uric acid
role and its importance as a protective antioxidant. Studies reported that uric acid is as
effective as antioxidant ascorbate in humans. While doing the estimation of total antioxidant
status in many diseased conditions, what we observe is researchers neglect the estimation of
uric acid though it is proved to be a powerful antioxidant. It clearly suggests that many clinical
researchers do not give much importance to very interesting compound uric acid. Less is
known about the beneficial effects of uric acid. On the other hand uric acid also acts as pro
oxidant in hydrophobic conditions. There is some controversy regarding uric acid acting as
antioxidant and pro oxidant. With this background we made an attempt to discuss and
summarize the protective role of uric acid in various disease conditions as an antioxidant and
harmful effects and also as risk factor for various diseases by acting as a pro-oxidant.
Uric Acid Chemistry and Its Formation
Uric acid is a heterocyclic organic compound with the formula C5H4N4O3 (2,6,8-trioxypurinne)
(figure 1) and a molecular weight of 168 Daltons2. Uric acid is the final metabolic product of
purine metabolism in humans. Many enzymes are involved in the conversion of the two
purine nucleic acids, adenine and guanine, to uric acid. Initially, adenosine monophosphate
(AMP) is converted to inosine by two different mechanisms; either first removing an amino
group by AMP deaminase to form inosine monophosphate (IMP) followed by
dephosphorylation with nucleotidase (NT) to form inosine, or by first removing a phosphate
group by nucleotidase (NT) to form adenosine followed by deamination to form inosine.
Guanine monophosphate (GMP) is converted to guanosine by nucleotidase (NT). The
nucleosides, inosine and guanosine, are further converted to purine base, hypoxanthine and
guanine, respectively, by purine nucleoside phosphorylase (PNP). Hypoxanthine is then
oxidized to form xanthine by xanthine oxidase, and guanine is deaminated to form xanthine
by guanine deaminase. Xanthine is again oxidized by xanthine oxidase to form the final
product, uric acid (figure 2).
The normal reference interval of uric acid in human blood is 1.5 to 6.0 mg/dl in women and
2.5 to 6.5 mg/dl in men. The solubility of uric acid in water is low, and in humans, the average
concentration of uric acid in blood is close to the solubility limit (6.8 mg/dL). When the level of
uric acid is higher than 6.8 mg/dL, crystals of uric acid form as monosodium urate (MSU)2.
Evolutionary Advantages of the Loss of Uricase
Several independent mutations in the uricase gene occurred during the evolution of hominids.
These mutations have been interpreted as clear evidence of an important evolutionary
advantage for the early primates that had increased UA3,4,5. As purine degradation is much less
complete in higher animals than in others, it is obvious that certain enzymes had been lost
during animal evolution and it is assumed that it provided some evolutionary advantage6.
On the other hand, if UA was a harmful/waste product, it would not explain how the kidneys
recover 90% of filtered UA7, instead of eliminating it. The evolution of hominids and the
physiology of renal urate balance indicate that uric acid is something beneficial that we must
retain instead of something harmful that has to be removed. These facts have led various
authors to propose some hypotheses, on the evolutionary advantages of the loss of uricase
and the subsequent increase in UA.
Since the discovery of antioxidant property of uric acid in 1981, it is believed that high blood
levels of uric acid in humans carry an evolutionary advantage and thus protects cardiac,
vascular, and neural cells from oxidative injury3. On the other hand, hyperuricemia even
without crystal deposition and gout is strongly associated with cardiovascular disease, kidney
disease, metabolic syndrome and hypertension, increasing the risk of mortality8. This dual
nature of uric acid is creating a paradox among researchers whether uric acid is an antioxidant
or an oxidant and raising a question is hyperuricaemia really an evolutionary advantage to
The oxygen consumed is utilized by mitochondria for oxidative phosphorylation and is
reduced to water in the electron transport chain (ETC). A small fraction of it is not used for this
purpose instead it is converted into free radicals ? which are harmful for the body when
present in excess. Free radicals are harmful for the body because they contain an unpaired
electron in their structure. These oxygen particles with an unpaired electron are called as
reactive oxygen species (ROS) and are proven to cause cell and tissue injury9.
Oxidative stress, which is defined as an imbalance between the pro-oxidant reactive species
and antioxidant molecules, both endogenous and exogenous, has been associated with many
non-communicable diseases, such as obesity, insulin resistance10 and diabetes11,
atherosclerosis12,13, autoimmune diseases14,15, neurodegenerative diseases16,17, chronic renal
disease18,19, different malignancies20,21, as well as in aging22 as a physiological process.
Definition of Antioxidant
Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing
agent. Oxidation reactions can produce free radicals, which start chain reactions that damage
cells. Antioxidants terminate these chain reactions by removing free radical intermediates and
inhibit other oxidation reactions by being oxidized themselves. So an antioxidant is a
molecule capable of slowing or preventing the oxidation of other molecules.
The antioxidant system can be weakened by a poor diet and a lack of nutrients, pathologic
conditions or pharmacological intervention, including intake of certain medications.
Uric Acid as an Antioxidant
Initially, uric acid was considered as an inert waste product that crystallizes at high
concentrations to form renal stones and provoke gouty arthritis. Subsequently, uric acid was
recognized to be a powerful antioxidant that scavenges singlet oxygen, oxygen radicals, and
peroxynitrite and chelates transition metals. Urate thus accounts for approximately half of the
antioxidant capacity of human plasma, and its antioxidant properties are as powerful as that
of ascorbic acid23, 24, 25.
The protection system to prevent and repair the oxidative damage includes antioxidant
enzymes like superoxide dismutase and glutathione peroxidase, free radical scavengers such
as vitamin E and the ?-carotenes in the lipid portion of the cells, ascorbic acid and UA in the
aqueous phase23. UA, being a powerful free radical scavenger as well as being able to act as
chelator of metal ions, such as iron and copper, by converting them to poorly reactive forms, is
one of the most important antioxidants in human biological fluids9. It is thought that UA
contributes to more than 50% of the antioxidant capacity of blood9,24. For this reason, Ames et
al., proposed26 that the loss of uricase expression and the subsequent increase in UA levels had
the evolutionary benefit of increasing antioxidant capacity, increasing the life expectancy of
hominids and decreasing age-specific cancer rates. The loss of uricase could be associated with
the previous loss of capacity to synthesize vitamin C5, 25 which occurred 40?50 million years
ago due to a mutation in L-gulono-lactone oxidase, in a period in which the primates of the
epoch ate large quantities of vitamin C in their diet, so it was an inoffensive mutation4, 5. With
a lower ingestion of vitamin C in later epochs and the subsequent loss of antioxidant capacity,
could be compensated by the increase in uric acid concentration due to loss of uricase activity5.
Protective (Antioxidant) Functions of Uric Acid
It has been hypothesized that the antioxidant properties of uric acid might be protective
against aging, oxidative stress, and oxidative injury of cells, including cardiac, vascular, and
neural cells (figure ? 3). Therefore uric acid has some beneficial effects. Less is known about
the beneficial effects of uric acid. Uric acid may function as a powerful antioxidant, and
possibly one of the most important antioxidants in plasma26-28. Watanabe et al23 has
suggested that hyperuricemia maintains blood pressure during low salt intake environments,
which may have provided a survival advantage during the course of primate evolution.
Therefore, many researchers thought that hyperuricemia is an evolutionary advantage to
humans developed due to the antioxidant properties of uric acid.
Urate (the soluble form of uric acid in the blood) can scavenge superoxide, hydroxyl radical,
and singlet oxygen and can chelate transition metals. Peroxynitrite is a particularly toxic
product formed by the reaction of superoxide anion with nitric oxide that can injure cells by
nitrosylating the tyrosine residues (nitrotyrosine formation) of proteins. Uric acid can also
block this reaction29. Hink et al30 reported that uric acid may also prevent the degradation of
extracellular superoxide dismutase (SOD3), an enzyme critical in maintaining endothelial and
vascular function. SOD3 is an extracellular enzyme that catalyzes the reaction of superoxide
anion (O2-.) to hydrogen peroxide (H2O2). The removal of super oxide anion (O2-.) by SOD3
prevents the reaction and inactivation by O2-. of the important endothelial vasodilator, nitric
oxide (NO). SOD3, by removing O2-., Therefore helps to maintain NO levels and maintain
endothelial function. Normally, SOD3 is inactivated in the presence of H2O2, suggesting a
feedback inactivation of the enzyme. However, uric acid blocks SOD inactivation by H2O2 by
regenerating SOD3 with the production of a urate radical30. This latter radical, although
potentially a pro-oxidant, has been found to be markedly less reactive than classic oxidants
and can be rapidly regenerated back to urate in the presence of ascorbate31.
Ames et al26 hypothesized that the uricase mutation occurred during early hominoid evolution
because the antioxidant action of uric acid may have provided an evolutionary advantage and
that this may account for the greater longevity of humans and the great apes compared with
most other primates. The increase in serum uric acid in subjects with cardiovascular disease
might therefore reflect a compensatory mechanism to counter the oxidative stress that occurs
in these conditions32.
Serum uric acid is considered as a useful biomarker for mortality in high-risk patients with
acute coronary syndromes and heart failure and in patients with hypertension33. Despite
emerging results on uric acid and its association with incident renal and cardiovascular
outcomes, the beneficial role of reducing uric acid levels on cardiovascular risk, as well as on
the progression of kidney diseases, is not established yet34. However, there is some evidence
to suggest the potential beneficial effect of reducing uric acid levels in humans.
Uric Acid as Surrogate Marker
It is also reported that uric acid may play an important role in diagnosis, prognosis and
therapy monitoring. Serum uric acid is a good indicator of the oxidative stress which is
involved in development of cardiovascular disorders, obesity, impaired glucose tolerance,
hypertension and hyperlipidemias. Hyperuricemia is not directly responsible for vascular
injury and increased risk for cardiovascular or cerebrovascular disease but simply represents a
surrogate marker for high levels of damaging oxidative stress associated with increased
xanthine oxidase activity. Indeed, hyperuricaemia is a significant predictor of disease state
and progression of chronic heart failure35. Uric acid is not only recognized as a marker of
oxidative stress, it also has a protective role. As described earlier it acts an antioxidant which is
involved in clinical investigations of therapy for cerebrovascular disorders in combination with
the anticoagulants. The assessment of UA is widely available at low cost, which may be an
advantage for widespread determination of this marker35.
Uric Acid and Bone Mineral Density
Oxidative stress has been linked to osteoporosis. Serum uric acid, a strong endogenous
antioxidant, has been associated with higher bone mineral density (BMD), lower bone
turnover and lower prevalence of fractures in a large cross-sectional study of men. Recently,
another cross-sectional study done in female subjects also revealed that uric acid has
protective role in bone mineral density. A very recent study done by Makovey J et al., revealed
that women with higher UA levels had significantly higher absolute BMD measures at all
skeletal sites36. Therefore, higher serum UA levels appear to be protective for bone loss in
periand postmenopausal women and this relationship is not affected by changes in body
Uric Acid in Neurological Disorders
Uric acid is known to have powerful antioxidant effects capable of neutralizing large amounts
of free radicals. The antioxidant activity of UA also occurs in the brain, being a protector for
several diseases such as Parkinson?s disease, Alzheimer?s, multiple sclerosis and associated
with a low level of uric acid. Uric acid possess beneficial role in some neurological disorders;
the argument in support of this hypothesis results from the low levels found in patients with
diverse neurological disorders. Higher concentration of UA is associated with lower risk of
development of Parkinson?s disease and a favorable effect at the disease progression
Recently, uric acid has been shown to play a role in innate immune responses to infection and
other injury. However at this moment in time, the potential benefits of a relatively high level
of uric acid are vastly outweighed by its adverse effects2.
It is not clear, whether uric acid would be a causal factor or an antioxidant protective response
against oxidative stress. While chronic high uric acid concentrations are associated to
increased risk for coronary artery disease (CAD), acute elevations seem to provide antioxidant
protection. Uric acid has a protective action in vitamins C and E with the stabilizing activities in
these vitamins39. On the top of it, the presence of ascorbic acid in plasma is required for the
antioxidant effect of uric acid.
Most authors do not consider uric acid as a detrimental factor to the body health, because of
its antioxidant function. Available data suggest that uric acid acts not only as an antioxidant
but depending on the chemical milieu, it may also act as pro oxidant. On one hand, in the
extracellular environment, urate can scavenge hydroxyl radical, singlet oxygen, and
peroxynitrite, especially when combined with ascorbic acid or thiols35,39. On the other hand,
uric acid loses its antioxidant ability in the hydrophobic environment. Moreover, it can form
free radicals either alone or in combination with peroxynitrite. Different mechanisms have
been proposed as explanations of paradoxical associations of uric acid, but the role of uric acid
as a causal, compensatory, or coincidental risk factor remains unclear. As there is tremendous
complexity in these disorders, an unambiguous common pathogenic feature for all of them is
an involvement of oxidative stress, conformational changes in proteins due to oxidative stress
and lipids as well as redox-dependent low-grade inflammation39.
Harmful Actions of Uric Acid
Growing epidemiological and clinical evidences suggest that hyperuricaemia might be a risk
factor for cardiovascular disease, where enhanced oxidative stress plays an important
pathophysiological role. The apparent paradox between protective and toxic effects of UA is
supported by clinical evidence that antioxidant compounds may become pro-oxidant
compounds in certain situations, particularly when they are present in blood at abnormally
high levels. Hyperuricemia has detrimental effects for multiple organ systems. Uric acid is
mainly known for its harmful effects such as gout and uric lithiasis, as well as its association
with hypertension, renal disease, metabolic syndrome and, cardiovascular disease (figure ?
3). It has also been hypothesized that hyperuricaemia might be involved in chronic heart
failure and metabolic syndrome.
Uric Acid in Hypertension and Cardiovascular Disorders
Hypertension is a multi-factorial process, prevalent in developed as well as in developing
countries. These complex changes are consistent in the view that essential hypertension is
associated with an abnormal level of antioxidant status. Some studies find that hyperuricemia
can be predictive for the development of hypertension, renal disease, and cardiovascular
disease despite controlling for associated risk factors. This raises the possibility that uric acid
may have a pathogenic role in hypertension and cardiovascular disease40.
High plasma uric acid levels are positively associated with increased incidences of
hypertension in adults41,42. More specifically, plasma uric acid levels significantly predict
diastolic hypertension, but not systolic hypertension43,44. This may be due to damage of small
renal vessels by increased uric acid levels, which leads to irreversible salt sensitive
hypertension. This salt sensitive hypertension persists regardless of uric acid levels23. However,
this association decreases as patient?s age increases and is not found in elderly patients45-48.
When hypertension develops in the elderly, other pathophysiological mechanisms such as
decreased arterial compliance may play a larger role in hypertension than hyperuricemia48.
The association of hyperuricemia and hypertension can be found in babies with low birth
weight. It is reported that low birth weight babies have an increased risk of hypertension at a
later stage of life, and is associated with high levels of uric acid49.
Hyperuricemia has also been established as an independent predictor of microalbuminuria50
and renal dysfunction51-53. In healthy normotensive individuals, increased uric acid levels
correlate with decreased kidney function. Both interstitial and vascular inflammation may also
occur. Thus, high levels of uric acid can induce a vasoreactive hypertension, which can further
develop into kidney-dependent hypertension54.
Increased serum uric acid concentration is associated with variables elevation of which worsen
cardiovascular prognosis, including blood pressure55 body weight and plasma cholesterol, and
with insulin resistance42,56,57. Nonetheless, large epidemiological studies that examined the
possible direct relationships between serum UA and cardiovascular outcomes have produced
inconsistent results55,58-60. For the preceding reasons, raised serum UA should not be
considered an independent risk factor for cardiovascular disease or heart failure. Increased
serum UA concentration may well be an innocent bystander associated with deleterious
processes including increased reabsorption of filtered sodium in the proximal tubule of the
nephron61 and insulin resistance, or it may constitute a compensatory response to oxidative
Although several studies have found that higher UA is an independent risk factor for cardio
vascular disorders (CVD) and mortality in subjects with cardiovascular risk profile. A negative
prognostic factor for survival in heart failure patients is still controversial whether high uric
acid is a compensatory attempt to counteract increased oxidative stress, an independent
cause of CVD, or just a condition associated with other well-established risk factors such as
hypertension, diabetes, and an accelerated clinical evolution of the disease26-29. Some authors
suggested that high UA levels may promote the hypertensive organ damage, exerting a
deleterious effect on endothelial function. However, these findings related to uric acid
attributable to excess mortality risk is particularly evident in women, older persons, and
subjects with pre-existing CVD24, 45.
Uric Acid in Ischemia Reperfusion Injury
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a
period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during
the ischemic period creates a condition in which the restoration of circulation results in
inflammation and oxidative damage through the induction of oxidative stress rather than
restoration of normal function. Reperfusion therapy is medical treatment that restores blood
flow through blocked arteries, typically after a heart attack (myocardial infarction). Categories
of reperfusion therapy thus include clot-busting (thrombolytic) drugs and procedures to open
arteries with stents, or to graft arteries around blockages63. These interventions have become
so central to the modern treatment of acute myocardial infarction64,65.
In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product
of ATP metabolism. During prolonged ischemia the enzyme xanthine dehydrogenase is
converted to xanthine oxidase as a result of the higher availability of oxygen. This enzyme
uses molecular oxygen as its electron acceptor, leading to the generation of hydrogen
peroxide and superoxide anion, toxic oxygen species that can be further metabolized to the
highly reactive hydroxyl radical. Xanthine oxidase also produces uric acid, which may act as
both a pro-oxidant and as a scavenger of reactive species such as peroxynitrite63,66. Excessive
nitric oxide produced during reperfusion reacts with superoxide to produce the potent reactive
species peroxynitrite. Such radicals and reactive oxygen species attack cell membrane lipids,
proteins, and glycosaminoglycans, causing further damage. They may also initiate specific
biological processes by redox signaling.
Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due
to increased permeability of capillaries and arterioles that lead to an increase of diffusion and
fluid filtration across the tissues. These "activated" endothelial cells produce more reactive
oxygen species but less nitric oxide following reperfusion, and the imbalance results in a
subsequent inflammatory response66. Further this process is aggravated by the formation of
uric acid because of the increased activity of xanthine oxidase enzyme. The inflammatory
response is partially responsible for the damage of reperfusion injury. White blood cells,
carried to the area by the newly returning blood, release a host of inflammatory factors such
as interleukins as well as free radicals in response to tissue damage67. The restored blood flow
reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma
membrane. Damage to the cell's membrane may in turn cause the release of more free
radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis.
White blood cells may also bind to the endothelium of small capillaries, obstructing them and
leading to more ischemia67.
Uric Acid and Inflammation
The role of uric acid in the process of atherosclerosis and atherothrombosis is controversial.
Epidemiological studies have recently shown that UA may be a risk factor for cardiovascular
diseases and a negative prognostic marker for mortality in subjects with pre-existing heart
failure. Researchers have suggested that the higher UA levels in subjects with CVD might be a
compensatory response designed to counteract excessive oxidative stress32. This theory has a
strong rationale in the biochemical characteristics of uric acid as anti-oxidant and is supported
by pre-clinical studies performed in vitro and in experimental animals9. However, the role of
UA in humans is still uncertain. A crude correlation between serum C-reactive protein and UA
levels has been found in a German population-based survey68, and a significant positive
correlation between UA and inflammation was found in a small clinical series of heart failure
patients69,70. Studies have demonstrated that after cellular death or injury, the degradation of
nucleotides into UA serves as an endogenous ?danger signal? for the maturation and
immunostimulatory action of dendritic cells71. In experimental studies, UA stimulates the
release of chemokine monocyte chemoattractant protein-172 and interleukin-1 (TNF-a)
synthesis73. In spite of the evidence that UA might contribute to the development of human
vascular disease and atherosclerosis through a pro-inflammatory pathway, the relationship
between UA and inflammation has been little investigated.
Moreover, across the uric acid quintiles, it is reported that progressive increase in the
percentage of subjects with abnormally high levels of IL-6 and CRP, which are considered solid
markers of inflammation in clinical practice. These findings suggest that the relationship
between UA and inflammatory markers is linear across the entire range of uric acid and that
such a relationship may be clinically relevant even in subjects with UA within the normal
range. However, the nature of such a relationship remains unknown. Actually, a significant
linear trend was also detected within the uric acid ?normal range?. These findings suggest that
UA is not only a marker of catabolic rate but also might be actively involved in systemic
inflammation, which an important component of the causal pathway is leading to
hypertension, vascular diseases, and renal failure70?73.
Uric Acid and Type 2 Diabetes
It is has long been hypothesized that hyperuricemia might be a risk factor for the
development of type 2 diabetes, but the casual association between hyperuricemia and type 2
diabetes remains controversial. Since elevated serum uric acid levels are often associated with
established type 2 diabetes risk factors, such as alcohol consumption and metabolic
syndrome, it is still unclear whether serum uric acid is merely a risk marker or an independent
risk factor for diabetes74.
Some researchers have proposed that hyperuricemia-induced oxidative stress represents a
cause of the metabolic syndrome75,76. Hyperuricemia has been found to be associated with
obesity and insulin resistance, and consequently with type 2 diabetes75, 77, 78.
Metabolic syndrome, type 2 diabetes, and atherosclerotic vascular disease are not only
characterized by various established but also emerging risk factors, and interestingly, these
three disorders have several risk factors in common. Very recently, several well-designed
prospective studies79-81 provided stronger evidence concerning the relationship between high
serum uric acid level and the risk of type 2 diabetes. All these prospective studies adjusted for
metabolic syndrome components to validate an independent association between uric acid
and diabetes, which was not sufficiently demonstrated previously.
Several underlying mechanisms might be involved in the association between hyperuricemia
and the development of type 2 diabetes. Hyperuricemia has been shown to induce endothelial
dysfunction and to reduce the production of nitric oxide40,82. Nitric oxide reduction could lower
insulin stimulated glucose intake in skeletal muscle, which contributes to insulin resistance
and thus diabetes. In addition, hyperuricemia is associated with oxidative stress8,83 which
plays an important role in the pathogenesis of type 2 diabetes. These experimental evidence
supports serum uric acid as a causal factor of diabetes.
Uric Acid and NAFLD
NAFLD is now considered a part of the metabolic syndrome, a clustering of cardiovascular
disease risk factors closely associated with insulin resistance and many endocrine
derangements including glucose homeostasis and central obesitiy84 -87. It has been reported
that hyperuricemia is related to insulin resistance and associated conditions88, 89 but its
relationship with NAFLD is not well known. One recent study suggested that hyperuricemia
was significantly associated with NAFLD, but the limitation of its cross-sectional study design
did not permit a conclusive evaluation for its causal relationship89. Insulin resistance and
hyperuricemia occur frequently in patients with NAFLD90,91. The close relationship between
insulin resistance and hyperuricemia suggests that hyperuricemia can contribute to the
development of NAFLD91. The mechanism which is involved in the association of NAFLD and
hyperuricemia was also uncertain.
Uric acid can act as either antioxidant or pro-oxidant depending on its circumstances,
especially on the availability of lipid hydro peroxides. From the available data it is evident that
a rise in uric acid represents an attempted protective response by the host and also uric acid
may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within
the cell). As uric acid is involved in a complex reaction with several oxidants and may have
some protective effects under certain conditions. Uric acid is an antioxidant only in the
hydrophilic environment, which is probably a major limitation of the antioxidant function of
uric acid. Soluble uric acid can also mediate the generation of radicals and function as a
prooxidant. These mechanisms by MSU or soluble uric acid found in gout may also contribute to
the development of vascular diseases seen in patients with hyperuricemia. However, current
models of the pathophysiological mechanisms of uric acid are not yet fully sufficient to explain
whether hyperuricaemia is really an evolutionary advantage for humans. Further research is
needed to better understand the biological roles of uric acid, and identify its clear role in the
pathophysiology of hyperuricemic related diseases.
List of abbreviations used: UA ? uric acid; MSU ? monosodium urate; AMP - adenosine monophosphate; IMP - inosine
monophosphate; NT ? nucleotidase; GMP - Guanine monophosphate; PNP - purine nucleoside phosphorylase; ETC - electron
transport chain; ROS - reactive oxygen species; SOD ? superoxide dismutase; BMD - bone mineral density; CVD - cardio
vascular disorders; NAFLD ? non alcoholic fatty liver disease
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