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6 January 2025

Antioxidant Properties of Albumin and Diseases Related to Obstetrics and Gynecology

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and
1
Department of Obstetrics and Gynecology, Aichi Medical University School of Medicine, Aichi 480-1195, Japan
2
Department of Dental Anesthesiology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8501, Japan
3
Departments of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
*
Authors to whom correspondence should be addressed.
Antioxidants2025, 14(1), 55;https://doi.org/10.3390/antiox14010055
This article belongs to the Special Issue Oxidative-Stress in Human Diseases—3rd Edition
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Abstract

Albumin, the most abundant protein, contributes significantly to various physiological processes, indicating its multifunctional properties. It has drawn the attention of scientists and physicians because of its primary role in maintaining osmotic pressure and involvement in transporting numerous small molecules, including hormones, fatty acids, and drugs. A growing body of evidence has recently illustrated an additional aspect of albumin’s antioxidant properties. Therefore, based on recent research findings, this review article delves into the molecular and biochemical aspects of albumin’s antioxidative capabilities. We highlight the multifaceted significance of proteins in oxidative stress and their relation to pathologies in obstetrics and gynecology. In particular, we focused on preeclampsia, in which oxidative stress is closely involved in the pathogenesis, and renal dysfunction leads to increased albumin excretion into the urine, resulting in hypoalbuminemia. In addition, we discussed the role of albumin in preeclampsia pathogenesis, diagnosis, and patient prognosis. Understanding the antioxidant properties of albumin opens new avenues for therapeutic intervention and sheds light on novel strategies for combating preeclampsia associated with oxidative damage. In this study, we employed the PubMed database to search for articles that assessed the antioxidant properties of albumin, with a specific focus on obstetric diseases, particularly preeclampsia. The last update of the search was conducted in November 2024.

1. Introduction

Albumin is a multifunctional serum protein that maintains human physiology [1]. As the most abundant protein, its significant contributions to various physiological processes underscore its multifunctional nature [1]. Scientists and physicians have been drawn to albumin because of its primary role in maintaining osmotic pressure [2] and its involvement in transporting numerous small molecules [3,4,5,6], including hormones, fatty acids, and drugs [3,5]. A growing body of evidence has recently highlighted its functional and antioxidant properties [7,8,9,10,11,12]. Regarding the antioxidant properties of albumin, functions such as the neutralization of free radicals [1], protection of antioxidants [13,14,15], transport of antioxidants [16], and interaction with agents [17,18] have been identified.
The term “antioxidant” is synonymous with protection against oxidative stress, a phenomenon characterized by the excessive production of reactive oxygen species and free radicals that lead to cellular damage and tissue injury [19,20,21]. Many antioxidants act as scavengers of harmful species, thereby neutralizing their detrimental effects [1]. Despite being primarily recognized for its transport functions, albumin has emerged as a significant player in the body’s defense against oxidative stress [16,22,23,24].
This review article delves into the molecular and biochemical aspects of albumin’s antioxidative capabilities, drawing upon recent research findings. It highlights the multifaceted significance of proteins in the context of oxidative stress and their relationship to pathologies in obstetrics and gynecology. Providing a comprehensive overview of albumin’s characteristics, general functions, and its newfound role as an antioxidant has become increasingly critical. Within this context, we describe the structural features that enable albumin to engage in antioxidative activities, explore the mechanisms through which it combats oxidative stress, and discuss the potential implications for women’s health. Additionally, we examine the role of albumin in obstetric and gynecological diseases. In particular, we focused on preeclampsia, in which oxidative stress is closely involved in the pathogenesis, and renal dysfunction leads to increased albumin excretion into the urine, resulting in hypoalbuminemia. We discussed the role of albumin in preeclampsia pathogenesis, diagnosis, and patient prognosis.
In this study, we employed the PubMed database to search for articles that assessed the antioxidant properties of albumin, with a specific focus on obstetric diseases, particularly preeclampsia. The search utilized combinations of the following terms: “antioxidant albumin”, “oxidative stress”, “inflammation”, “preeclampsia”, “vascular endothelial dysfunction”, “renal dysfunction”, and “chronic kidney disease”. The last update of the search was conducted in November 2024.

2. Albumin’s Previously Known Characteristics, Functions, and Roles

Albumin is a vital and highly versatile protein found in the plasma of mammals, including humans. It is the most abundant plasma protein in the human circulatory system, with a molecular weight of approximately 66,000 Da, contributing to approximately 60% of the total plasma protein content [1,25]. Albumin is synthesized in the liver at up to 0.7 mg/h per gram (10–15 g/day) and secreted continuously without storage [11,26,27]. It is a critical regulator in many physiological and pathological aspects, such as colloid osmotic pressure, nutritional status, and inflammation [28,29,30,31]. Its kinetics depend on its synthesis, distribution within interstitial tissues and intravascular compartments, and excretion, indicating its significance in maintaining the colloid osmotic pressure of the blood, which is essential for proper fluid distribution between the bloodstream and tissues [29].
Albumin is a globular protein with a distinct three-dimensional structure consisting of a single polypeptide chain with multiple subdomains [4,7,11]. Their unique structures allow them to interact with various molecules, resulting in a wide range of functions. One of the primary roles is its action as a carrier or transporter targeted to variable substances, and it binds to a diverse array of small molecules, including fatty acids, hormones, bilirubin, drugs, and ions [4,32,33,34,35,36,37]. The albumin binding to these substances facilitates the appropriate and secure transportation of the albumin-conjugated complex into the bloodstream. This process determines the efficient delivery of molecules to target tissues and organs [3,27].
Albumin is critical in maintaining oncotic or colloid osmotic pressure in blood vessels [28,38,39,40]. The oncotic pressure gradient caused by albumin is essential for preventing excessive fluid leakage from the blood into the surrounding interstitial tissues, helping to maintain an appropriate blood volume and pressure. Therefore, albumin regulates the distribution of water, ions, and other molecules [41,42]. Its abundance, unique structure, and ability to transport various molecules make it indispensable for maintaining stable functions in the human body.
Albumin, with its diverse functions and roles, is indispensable for sustaining life. In conclusion, its multifaceted contributions underscore its significance in various biological processes, emphasizing its irreplaceable role in maintaining stable functions within the human body.

3. Albumin’s Antioxidant Properties

Previous studies have demonstrated the antioxidant properties of albumin, including its ability to neutralize harmful reactive oxygen species and free radicals, thereby protecting cells and tissues from oxidative stress. These findings may provide new insights into its significance in various pathophysiological conditions. This section summarizes previous studies and their results regarding human serum albumin as an antioxidant. Additionally, as shown in Table 1, it discusses the direct effects of albumin on oxidants and its indirect actions in supporting other antioxidants (Table 1). Furthermore, we address the specific origins of albumin beyond humans, such as bovine serum albumin.
Table 1. Albumin’s antioxidant properties.

3.1. Neutralization of Free Radicals by Albumin

Albumin directly or indirectly neutralizes reactive oxygen species and free radicals, reducing oxidative stress in living cells and tissues.
Albumin stabilizes hydroxyl radicals, a highly reactive radical, resulting in oxidative stress reduction in cells and tissues [16,22,43,44,45,46,47,48,49,58]. The reduced form of human serum albumin, also known as reduced human albumin (reduced albumin; human mercapto-albumin: HMA), directly reacts with hydroxyl radicals and is converted to an oxidized form (oxidized albumin; human non-mercapto-albumin: HNA) [8,11,24,43]. This process involves a hydroxyl radical neutralization caused by Cysteine-34 within human serum albumin as a critical cysteine residue for its function [1,43,50,62,63]. When free radicals, such as the hydroxyl radicals, are encountered, the Cysteine-34′s thiol group instantly reacts with them [43], indicating the mechanism highlighting the significance of Cysteine-34 in albumin’s role as a potent antioxidant in biological systems. In contrast, the counteraction of Cysteine-34 with radicals facilitates the conversion of HMA to HNA [16,59,64,65,66].
Albumin reacts with peroxyl radicals, resulting in the inactivation of the radicals [51,67]. Highly reactive peroxyl radicals induce lipid peroxidation and damage cell membranes and biological molecules, suggesting that albumin protects cells from these radicals. In addition, albumin neutralizes peroxyl radicals owing to its ability to bind hydrophobic molecules, such as fatty acids and pharmacological agents, as albumin-bound hydrophobic molecules are likely not utilized for lipid peroxidation processes.
Albumin also indirectly neutralizes highly reactive singlet oxygen, which mediates oxidative damage to biomolecules, including lipids, proteins, and DNA, through its ability to bind hydrophobic molecules, similar to its effect on peroxyl radicals [53].
Albumin’s antioxidative reactions involve scavenging superoxide radicals, thus mitigating oxidative damage. Additionally, albumin has been observed to inhibit NADPH oxidase, an enzyme responsible for generating superoxide in cells. By inhibiting membrane recruitment of the NADPH oxidase cytosolic submit p47phox, albumin further contributes to the reduction of superoxide production, helping to maintain a balance in oxidative processes [54,55]. Albumin demonstrates antioxidant effects by directly interacting with superoxide and by inhibiting the activity of NADPH oxidase, ultimately playing a protective role against oxidative stress.
Albumin acts as a potent antioxidant by directly neutralizing hydroxyl radicals and peroxyl radicals, inhibiting lipid peroxidation, and scavenging superoxide radicals. The critical cysteine residue, Cysteine-34, plays a key role in these antioxidative reactions. Additionally, albumin indirectly neutralizes singlet oxygen by binding hydrophobic molecules. Moreover, albumin inhibits NADPH oxidase, reducing superoxide production and contributing to the overall protection against oxidative stress in living cells and tissues.

3.2. Protection of Antioxidants by Albumin

Albumin plays a crucial role in protecting dietary antioxidants. Albumin stabilizes dietary antioxidants, including L-ascorbic acid (vitamin C), α-tocopherol (vitamin E), procyanidin B3, β-carotene, and astaxanthin, resulting in the prolongation of their antioxidant property. Indeed, ovalbumin counteracts oxygen-derived free radicals by binding to dietary antioxidants [13]. Albumin stabilizes (-)-epigallocatechin gallate, a component and antioxidant in green tea, in human serum [14]. In addition, bovine serum albumin stabilizes the antioxidant blueberry anthocyanins and enhances their antioxidant activity [15]. These results indicate the role of dietary antioxidants in oxygen-derived free radicals.

3.3. Transport of Antioxidants by Albumin

Albumin is responsible for transporting lipids and easily oxidizable antioxidants into the blood, allowing them to reach their destinations and exert their effects before undergoing oxidation. In the bloodstream, albumin binds to various substances, including fatty acids, bilirubin, bile acids, calcium, iron, copper, zinc, other cations, drugs, and tryptophan [16]. Albumin is a crucial ligand for free fatty acids, particularly polyunsaturated ones. This binding prevents peroxidation and reactive oxygen species formation. Lipid affinity also varies; for instance, proatherosclerotic lysophosphatidylcholine and lysophosphatidic acid exhibit a higher affinity for the oxidized form, whereas antiatherosclerotic derivatives of eicosapentaenoic and docosahexaenoic acids preferentially bind to the reduced albumin form [68]. It is essential to spotlight arachidonic acid and its derivatives to delve deeper into the intricate relationship. Arachidonic acid, a prominent polyunsaturated fatty acid, is a pre-cursor for synthesizing eicosanoids, which are active compounds. These eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, play pivotal roles in various physiological processes, such as inflammation and immune response [69]. The dynamic interaction between albumin and arachidonic acid derivatives underscores a nuanced regulation of lipid metabolism and signaling pathways. Understanding these intricacies sheds light on the multifaceted nature of albumin’s role in maintaining the delicate balance between proatherosclerotic and antiatherosclerotic processes, offering valuable insights into the broader landscape of cardiovascular health.
In addition, albumin readily binds to metals in the blood. Notably, the binding properties of albumin demonstrate significant benefits, especially for metals, such as Cu2+ and Fe3+, which are highly pro-oxidative in their free forms. These metals interact with hydrogen peroxide in the free state, forming hydroxyl radicals with deleterious effects.
Through its binding properties, albumin may regulate the availability of these substrates and, among other actions, inhibit the pro-oxidative effects of metals and fatty acids [44].
Albumin serves as a crucial transporter for lipids and easily oxidizable antioxidants in the bloodstream, preventing peroxidation and reactive oxygen species formation. It binds various substances, including fatty acids, bilirubin, bile acids, and metals like Cu2+ and Fe3+, regulating their availability and inhibiting their pro-oxidative effects. The dynamic interaction between albumin and arachidonic acid derivatives highlights its nuanced role in lipid metabolism and signaling pathways, offering insights into cardiovascular health.
An important consideration is the redox state of albumin, which may differentially influence its interactions with various substances. For example, reduced albumin exhibits stronger binding affinity for Cu2+ and can transport nitric oxide, whereas oxidized albumin demonstrates a higher affinity for lipid peroxides. This dual behavior highlights the nuanced role of albumin in modulating oxidative stress. While the transport of lipid peroxides by oxidized albumin could potentially exacerbate oxidative stress, it may also serve as a protective mechanism by preventing their accumulation in vulnerable tissues. These contrasting effects underscore the complexity of albumin’s role in oxidative stress regulation and warrant further exploration.

3.4. Albumin Interaction with Agents

Albumin binds to numerous agents and facilitates their transport and distribution. This binding influences the metabolism and elimination of specific agents, mitigating harmful side effects from oxidation.
Quercetin, a polyphenol belonging to the flavonoid group, is a natural plant compound characterized by a yellow crystalline structure with a flavone backbone. It is naturally found in various foods, including citrus fruits, apples, onions, broccoli, kale, tea, red wine, and berries. Quercetin protects cells from oxidative stress and reduces the damage caused by reactive oxygen species, contributing to overall cellular health because of its potent antioxidant properties. Albumin binds quercetin and prevents its oxidation [17,18,60]. It has been reported that tea catechins bind to albumin, thereby enhancing its oxidative effect [61].

5. Conclusions

Preeclampsia enhances the levels of reactive oxygen species, free radicals, and inflammation activity, resulting in vascular endothelial dysfunction. Currently, low-dose aspirin therapy [146,147,148] and statin therapy [149,150] are the most promising approaches for preventing preeclampsia. Recently, the antioxidant properties of albumin have gained attention, promoting our focus on its role in the pathogenesis of preeclampsia. Preeclampsia involves oxidative stress as an etiological factor and leads to hypoalbuminemia owing to urinary protein excretion. Furthermore, the inflammation associated with preeclampsia elevates cytokine levels, suppressing albumin production and exacerbating hypoalbuminemia. This hypoalbuminemia, in turn, increases oxidative stress, contributes to vascular endothelial dysfunction, and underlines the fundamental pathophysiology of preeclampsia. Potential treatment strategies involving albumin for preeclampsia include albumin replacement and prevention of renal excretion. However, replacement therapy may have limited efficacy in cases with significant urinary albumin loss, becoming beneficial only if renal albumin excretion is effectively suppressed. Pregnant women with a history of proteinuria-associated preeclampsia may benefit from preventive measures, particularly if hypoproteinemia is observed prior to the onset proteinuria. At present, dietary modifications, such as restricting excessive calorie and salt intake, remain the only evidence-based intervention for renal protection in preeclampsia. Further research is essential to elucidate the relationship between preeclampsia and hypoalbuminemia. Additionally, women with a history of preeclampsia face a heightened risk of developing chronic kidney disease later in the future. Persistent urinary albumin secretion after delivery may exacerbate renal damage, potentially progressing to chronic kidney disease. Understanding the antioxidant properties of albumin not only provides new insights into the pathophysiology of preeclampsia but also opens avenues for innovative therapeutic strategies targeting oxidative damage in obstetric and gynecological disorders.

Author Contributions

Conceptualization, K.W. and H.K.; methodology, K.W. and H.K.; software, K.W. and H.K.; validation, K.W. and H.K.; writing—original draft preparation, K.W. and H.K.; writing—review and editing, K.W., H.K., T.O., K.S., S.K., and T.K.; project administration, K.W. and H.K.; funding acquisition, K.W. and H.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported in part by JSPS KAKENHI Grant Number. JP21K08949 and JK24K12544.

Conflicts of Interest

The authors certify that there are no conflicts of interest with any financial organization regarding the material discussed in the manuscript.

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