Clin. Lab. 2013;59:XXX-XXX ©Copyright
REVIEW ARTICLE
Human Serum Albumin and Its Relation with Oxidative Stress MUSTAFA ERINÇ SITAR, SEVAL AYDIN, UFUK ÇAKATAY Department of Medical Biochemistry, Cerrahpaşa Faculty of Medicine, Istanbul University, Fatih, 34098 Istanbul, Turkey
SUMMARY Human serum albumin, a negative acute phase reactant and marker of nutritive status, presents at high concentrations in plasma. Albumin has always been used in many clinical states especially to improve circulatory failure. It has been showed that albumin is involved in many bioactive functions such as regulation of plasma osmotic pressure, binding and transport of various endogenous or exogenous compounds, and finally extracellular antioxidant defenses. Molecules like transferrin, caeruloplasmin, haptoglobin, uric acid, bilirubin, α-tocopherol, glucose, and albumin constitute extracellular antioxidant defenses in blood plasma but albumin is the most potent one. Most of the antioxidant properties of albumin can be attributed to its unique biochemical structure. The protein possesses antioxidant properties such as binding copper tightly and iron weakly, scavenging free radicals, e.g., hypochlorous acid (HOCl) and Peroxynitrite (ONOOH) and providing -SH. Whether it is chronic or acute, during many pathological conditions, biomarkers of oxidative protein damage increase and this observation continues with considerable oxidation of human serum albumin. There is an important necessity to specify its interactions with Reactive Oxygen Species. Generally, it may lower the availability of pro-oxidants and be preferentially oxidized to protect other macromolecules but all these findings make it necessary that researchers give a more detailed explanation of albumin and its relations with oxidative stress. (Clin. Lab. 2013;59:xx-xx. DOI: 10.7754/Clin.Lab.2012.121115)
KEY WORDS
INTRODUCTION
albumin, oxidative stress, antioxidant defenses, cysteine 34
Recent researches and current information on albumin have increased considerably both in basic and clinical settings in the past decades. It is encouraging to observe that a search for publications on "albumin" in Pubmed, as updated in June 2013, yielded over 193000 items. Throughout medical history, albumin, one of the most abundant and crucial proteins found in human beings, has been the issue of interest and research. Some of its physiological properties have been recognized since the time of Hippocrates [1,2]. It is also probably the most studied of all proteins for its manifold functions which constitute the prime interest of scientists from many fields including biologists, biochemists, chemists, pharmacologists, and physicians for more than 150 years [3]. The modern use of human albumin was established during World War II due to demand for plasma substitutes by E.J. Cohn and colleagues at the Plasma Fractionation Laboratory of Harvard University Department of Physical Chemistry. Human plasma fractionation and concentrated serum albumin have been used for treatment of shock [4]. Thorn et al. used albumin as a thera-
LIST OF ABBREVIATIONS AOPP - Advanced Oxidation Protein Products H2O2 - Hydrogen Peroxide HSA - Human Serum Albumin HMM - High Molecular Mass IMA - Ischemia Modified Albumin LDL - Low Density Lipoprotein ROS - Reactive Oxygen Species SOD - Superoxide Dismutase
_____________________________________________ Review Article accepted November 28, 2012
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peutic agent to treat chronic nephritis in the 1940’s, as well [5]. The complete amino acid sequence of human and bovine albumin was published in 1975 by J. R. Brown and his collegues [6]. After the crystallographic structure of HSA (Human Serum Albumin) had been solved, rapid progress regarding albumin still continues every day from scientific to biotechnological perspectives.
Maintenance of Plasma Colloidal Osmotic Pressure Major plasma proteins consist of albumin, globulin, and fibrinogen fractions. Most capillary walls are relatively impermeable to these proteins in plasma, and the proteins therefore exert an osmotic pressure of about 25 mm Hg across the capillary wall keeping water in the circulatory system [23]. Albumin has a high capacity for binding water (18 mL/g), an intravascular residence time of 4 hours, presupposing physiological capillary permeability, and an in vivo half-life of 18 - 21 days [24-26]. Human serum albumin accounts for some 60% of the intravascular protein pool in healthy individuals, thereby being responsible for approximately 60% of plasma colloid oncotic pressure [2]. Albumin does not diffuse freely through intact vascular endothelium. Hence, it is the major protein providing the critical colloid osmotic or oncotic pressure that regulates passage of water and diffusible solutes through the capillaries [27]. It inhibits the passage of fluid from intravascular compartment to the interstitial tissue. Its remaining contribution to colloid oncotic pressure is due to the GibbsDonnan effect of attracting other active positive ions, further enhancing its water retaining effect [28].
Biochemical Aspects of Human Serum Albumin The concentration of albumin in plasma of healthy humans amounts to 440 - 660 mM (i.e., 30 - 45 g/L). This protein is synthesized in liver after loss of a 24-residue propeptide and immediately secreted into the bloodstream without being stored [1,11]. Extravascular colloid oncotic pressure in the liver is considered to be the main factor regulating its synthesis [12]. The entire process of synthesis and secretion of albumin is quite rapid, taking about 30 minutes [13,14]. In healthy adults, albumin synthesis occurs predominantly in polysomes of hepatocytes (10 - 15 g/day) and accounts for 10% of total liver protein synthesis. Between its birth and death, it makes ~15,000 trips around the circulation [1,11]. At the end of the entire process, albumin is usually degraded ubiquitously, in an amount comparable to that synthesised by the liver (10 - 12 g/24 hours) [14, 15]. Albumin is also a highly water soluble and relatively small (66 000 Da) globular protein. It lacks prosthetic groups or covalently bound carbohydrates or lipids. So, it is an abundant multifunctional non-glycosylated, negatively charged plasma protein, which is thought to be a negative acute-phase protein, as well [1,11,16]. It has three structurally homologous domains (I, II, III), each containing two sub-domains (A and B) (Figure 1) [17]. The subdomains move relative to one another by means of flexible loops provided by proline residues, which helps accommodate the binding of an array of substances, as does the flexibility provided by domain-linking disulfide bridges [18]. Most of the protein has an alpha helical structural integrity and is heart shaped which is also highly stabilized by disulphide bridges. Its 585 amino acids include 6 methionines, 18 tyrosines, 1 tryptophan, 17 disulfide bridges, and only one free cysteine, Cys34. In addition, an abundance of charged residues such as lysine and aspartic acid are present [19]. The disulphide bridges add substantially to the stability of the protein, explaining its relatively long biological half-life of about 20 days [20]. The 17 disulphide bridges inside the protein stabilize the tertiary structure at neutral pH and room temperature but do not prevent significant changes in shape and size as a function of pH and temperature [21,22].
Buffering Blood pH Human serum albumin develops reversible conformational isomerization with changes in pH. It has 16 histidine imidazole residues, which are responsible for the buffering function of this special protein [14,22,29]. Transport The dissociation constant Kd formulas are better located consecutively or side by side The protein is like a shuttling cargo of various endogenous and also exogenous compounds between liver and peripheral tissues. The flexibility of the albumin structure allows the protein to accommodate molecules of many different structures and also gives the capacity to bind and transport quite diverse metabolites [3,30]. Because of its high net charge, albumin possesses excellent binding capacities, among other things, for water, calcium, sodium, and trace elements. Albumin is also an important transport protein for plasma unesterified (free) fatty acids, indirect bilirubin, amino acids, and hormones (T4, gonadal steroids, etc.), as well as many of the most important pharmaceuticals [12]. Distribution throughout the organism and half-lives of many drugs, largely depend on albumin binding. Albumin binding of these pharmaceuticals is noncovalent and therefore reversible. Competition of medications for albumin binding sites may cause drug interaction by increasing or decreasing the free fraction of one of these drugs, thereby affecting their potency. The dissociation constant Kd for the release of the drug from albumin is defined as:
Functions of Human Serum Albumin Human serum albumin is known for its regulation of colloid osmotic pressure, buffering acid-base changes, transportation of a wide range of endogenous ligands and drugs, and potent antioxidant and free radical scavenging activities (Table 2).
[
] [ [
2
] ]
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ANTIOXIDANT ROLES OF ALBUMIN Table 1. Milestones of albumin history starting with Hippocrates up to the present decade. Name
Date
Incidence
Hippocrates
400 BC
Bubbles in urine, indicating chronic kidney disease [1]
Antoine F. Fourcroy
Early 1800’s
One class of three animal matters is albumin [7]
J. Berzelius
1812
Albumin determination in serum [7]
E. J. Cohn and his collaborators
1940’s
Plasma fractionation and concentration of Human Serum Albumin in Harvard Physical Chemistry Laboratory [4]
Peters T. Jr.
1950
Liver, as site of albumin synthesis [8]
J. R. Brown
1975
Complete amino acid sequence of human and bovine albumin [6,9]
Carter et al.
1989
Three-dimensional structure of human serum albumin [10]
Table 2. Multiple functions of human serum albumin in human physiology and pharmacology. Multiple Functions of Human Serum Albumin Maintenance of plasma colloidal osmotic pressure Transport - calcium, magnesium, free fatty acids, bilirubin, hormones, pharmaceuticals Buffering of blood pH Antioxidant effects
Figure 1. Heart shaped human serum albumin and its sub-domains.
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Figure 2. HSA and its relation with Free Radical Injury. Cysteine 34 is shown in blue color.
This can be rearranged as: [ [
ed forms in systemic circulation and the reduced form of the human serum albumin has been shown to be lower in patients with hepatic disorders, diabetes, and renal diseases [37]. Aerobic organisms survive in oxygen presence because they have evolved antioxidant defenses. The term ‘antioxidant’ is broadly used by food manufacturers, analytical chemists, pharmacists, physiccians and scientists but it is also quite difficult to describe. For a comprehensive definition, antioxidants are substances that delay or prevent oxidation of molecules even when they are present at low amounts compared to oxidizable substrates. These antioxidant defenses are categorized basically:
] ]
[
]
It is not the total drug concentration, but the concentration of the unbound drug that determines the biological response [31]. It is evident how albumin concentration may be important when administering drugs with a high-binding affinity, especially during acute pathological processes usually characterized by hypoalbuminemia. In these conditions, drug toxicity or even drug inefficiency may be observed [14,32].
(a) agents that catalytically remove Reactive Oxygen Species (ROS), such as the superoxide dismutase (SOD), superoxide reductase, catalase, and peroxidase enzymes; (b) agents that decrease ROS formation, e.g., mitochondrial uncoupling proteins, transferrin, haptoglobins, haemopexin, and metallotionin; (c) proteins that protect biomolecules against oxidative damage, e.g., chaperones; (d) physical quenching of ROS e.g., singlet O2 by carotenoids; (e) replacement of molecules sensitive to oxidative damage by resistant molecules, an example is fumarase C of E.Coli.
Antioxidant Effects When the cellular redox balance shifts towards oxidants, it is called oxidative stress A cellular redox regulation system is responsible for the modulation of redox homeostasis, which maintains the equilibrium between oxidants and antioxidants [33,34]. When the cellular redox balance shifts towards oxidants, it is called oxidative stress/damage [35,36]. Oxidative stress is believed to play a crucial pathophysiological role in a variety of diseases. Indeed oxygen can be considered a relatively toxic gas because it may lead to oxidation of essential cellular macromolecules. It is readily conceivable that the ligand binding properties of albumin may be altered during the development of these pathologies. Albumin exists in both reduced and oxidiz-
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PREANALYTICAL CONSIDERATIONS AND NITRIC OXIDE ASSAY
(f) ‘sacrificial agents’ that are oxidized by ROS to preserve more important molecules; examples are GSH, α-tocopherol, bilirubin, ascorbate, and urate [38] From hundreds of proteins found in plasma, albumin is by far the predominant antioxidant as expected from its amount. There are epidemiological studies showing an inverse relationship between serum albumin level and mortality risk in current medical literature [39,40]. For both the general population and diseased people, it has been presumed that the odds of death increase by about 50% for each 2.5 g/L decrement in the initial albumin level. Lower serum albumin has been accepted as a reliable indicator of malnutrition, inflammation, renal and hepatic diseases [16]. The beneficial effects of higher albumin concentration could be explained by unique antioxidative effects of this protein exerted in plasma, which is a body compartment exposed to continuous oxidative stress [41,42]. More than 70% of the free radical-trapping activity of serum is due to human serum albumin as assayed using the free radical-induced hemolysis test [43,44]. To give some specific examples of diseases, oxidative stress is enhanced in correlation with the level of renal dysfunction among patients with chronic renal failure. Plasma albumin has been found to undergo massive oxidation in primary nephrotic syndrome [45,46]. Albumin concentrations were found enhanced in sites of inflammation where the protein exerts its multiple antioxidant properties [47]. Free or loosely bound, redox-active transition metal ions (low molecular mass) are potentially extremely pro-oxidant, having the ability to catalyze the formation of damaging and aggressive ROS from much more innocuous organic and inorganic species [18]. In the presence of catalytic amounts of transition metal ions, particularly iron and copper, these species can generate the highly reactive hydroxyl radical by the Fenton reaction [48]. Oxidative damage by free radicals in biological systems is often linked to the Fenton reaction. The Fenton reaction is the one electron reduction of hydrogen peroxide (H2O2) by the transition metal ions such as iron and copper [37]. When bound to proteins, these metals are generally less susceptible to participate in Fenton reactions. In plasma, most of the copper is bound to ceruloplasmin, but a high percentage of the metal ion may exist bounded to albumin [47]. Several studies have shown an antioxidant property of albumin by binding copper using the copper-induced low-density lipoprotein (LDL) oxidation assay [49-52]. Regarding iron, proteins involved in its transport are transferrin, ceruloplasmin, and lactoferrin. Nonetheless, high concentrations of circulating albumin indicate that the protein might be able to scavenge some hydroxyl radicals produced from iron’s reaction with H2O2 [47]. In addition, in iron-overload disease, a significant amount of iron-bound albumin was reported [53]. HSA can limit damage caused by accidental biological contamination by other redox active metal ions such as vanadium, cobalt, and nickel, as well [18].
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Albumin is the most abundant high-molecular-mass (HMM) reduced thiol in human plasma that contains a single sulfhydryl group located at cysteine-34 [54]. Cysteine-34 in domain I of albumin is the binding site for a wide variety of biologically and clinically important small molecules [55-57]. This special cysteine residue in position 34 exposes a thiol (-SH) radical group, constituting the largest portion of free thiol in blood which is one of the main extracellular antioxidants [14, 58]. Due to the reduced Cys34, albumin is able to scavenge hydroxyl radicals [59]. According to Bourdon and his colleagues, Met and Cys accounted for 40 - 80% of total antioxidant activity of HSA. They concluded that Cys chiefly works as a free radical scavenger whereas Met mainly acts as a metal chelator [43,50,60]. From a clinical perspective, administration of albumin to a critically ill patient, during an acute pathological process usually increases the plasma concentration of thiols [61]. The thiol moiety of this particular Cys-34 is reactive and capable of thiolation (HSA-S-R) and nitrosylation (HSA-S-NO), processes that are thought to contribute to several in vivo functions [18]. In 1992, it was reported that nitric oxide (NO), whose half-life in vivo is 0.1 seconds, circulates in human plasma primarily in the form of S-nitrosoprotein. It is known that S-nitrosoproteins serve to transmit nitric oxide and S-nitrosoalbumin, being the most abundant of these proteins [62-64]. S-nitrosoalbumin has been shown to be an efficacious cytoprotective molecule in acute lung injury, as well as ischemia-reperfusion injury in heart and skeletal muscle. Unfortunately, only limited information is available on the cellular mechanism of such protection [65]. Advanced Oxidation Protein Products (AOPP) A new and original oxidative stress biomarker, referred to as advanced oxidation protein products, has been discovered in the plasma of chronic uremic patients in 1996. Witko Sarsat et al. showed that in vivo levels of AOPP strongly correlate with creatinine clearance, indicating that AOPP are excellent markers of chronic renal failure progression [66]. AOPP correspond to highly oxidized proteins, specifically to albumin, and might be formed during oxidative stress by reaction of plasma proteins with chlorinated oxidants (Figure 2). Thus, AOPP have been considered a novel marker of oxidantmediated protein damage [67]. Results of in vitro studies of mechanisms of AOPP production indicate that HOCl treated HSA can trigger an oxidative burst [68]. However, the mechanisms by which AOPP are degradeed and eliminated from circulation remain unclear [69]. Ischemia Modified Albumin (IMA) It is a well known fact that ischemia occurs when there is a supply-demand mismatch in blood flow of the tissue, and that albumin is the major extracellular plasma protein target of oxidative stress. In N-terminus region, human serum albumin consists of a sequence of amino acids N-Asp-Ala-His-Lys, which has high ability to bind transition metal ions such as cobalt, copper, and
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nickel [70]. In cases of insufficient reperfusion, albumin undergoes a conformational change and loses its ability to bind transitional metals. The increased generation of ROS can transiently modify the N-terminal region of albumin and produce an increase in the concentration of ischemia-modified albumin, which is considered a new marker for ischemia [71]. Therefore, IMA is the end product of oxidative stress and a form of HSA in which the N-terminal amino acids are unable to bind to transition metal ions [72,73]. The most important characteristic property that differentiates IMA from other cardiac ischemia markers is that it increases, in particular, in the early phase [74]. Various studies have shown that IMA increases within minutes after the onset of ischemia, remains elevated for 6 - 12 hours, and returns to normal within 24 hours [75]. IMA is a recently approved FDA (Food and Drug Administration) diagnostic biomarker that can detect myocardial ischemia within minutes so it may be enormously valuable to emergency physicians assessing patients presenting with chest pain but they require a better understanding of this marker before it is ready for “prime time” use [72]. Beside cardiovascular pathologies, IMA is also elevated in most patients with cirrhosis, acute infections and later stages of cancer; all these conditions are potent producers of ROS [76]. In addition to variable diseased states, other physiological conditions, such as exercise, minimal acidosis, obesity or slight dehydration also contribute to elevation of IMA levels [77]. This issue should always be kept in mind because it may lead physicians to false positive or over diagnosis.
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Challenges and Future Directions While many mechanisms were elucidated by the help of completed research, there are still many challenging areas regarding albumin. For instance, mechanisms of S-nitrosoalbumin have to be explained in a more reliable and specific manner from a pathophysiological point of view. Beside AOPP degradation and elimination from plasma, problems about stability of IMA and its lack of cardiospecificity have to be resolved as well, because different organs and cells have different levels of vulnerability to ischemia or ischemia-reperfusion injury. The clinical use of albumin solution over 50 years as a plasma volume expander and a supplement of total parenteral nutrition is a controversial issue to improve circulatory function. The relatively high cost of albumin and lack of clear mortality and morbidity benefit makes this issue more intricate and an ongoing seesaw evolution. For instance, clinical benefits of albumin infusion in sepsis, burn or acute respiratory distress syndrome patients continue to be debated. Many further studies and future efforts are required in order to determine the role of albumin and its clinical and diagnostic efficacy.
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Declaration of Interest: No potential conflict of interest relevant to this article is reported.
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Correspondence: Ufuk Çakatay Department of Medical Biochemistry Cerrahpaşa Faculty of Medicine Istanbul University Fatih, 34098 Istanbul, Turkey Tel.: + 90 212 414 30 00 / 21514 Fax: + 90 212 632 00 50 Email:
[email protected]
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