Human serum albumin

Cancer is the uncontrolled growth of cells with loss of differentiation and commonly with metastasis. Anticancer drugs are used to control the growth of cancerous cells. Oxaliplatin is a third-generation platinum-derived antineoplastic agent that has been proved effective mainly against advanced colorectal cancer (CRC). Oxaliplatin administration has an acute excitatory and sensitizing effect, including unpleasant cold allodynia in the distal extremities, mouth, and throat and usually associated with muscle cramps. However, the major side effect, a dose-limiting toxicity of the peripheral nerves, affects the sustainability of the planned treatment. Although these acute symptoms resolve within 1 week, severe chronic sensory neuropathy develops with the increasing cumulative dose and is characterized by distal paresthesia and numbness.[7][8] Drug  delivery  systems  aim to deliver the drugs over an extended duration or at a specific time during treatment. Therefore, the improvement of the efficiency and convenience of a drug release system is of paramount importance. In the past two decades, numerous nanoparticles (NPs) have been extensively explored in order to achieve precisely controlled drug delivery.[9] However, the application and development of high-efficiency drug release system are still limited due to a lacking of simple, stable and efficient drug delivery vehicle. Human serum albumin (HSA) is a highly water-soluble globular monomeric plasma protein with a relative molecular weight of 67 KDa, consisting of 585 amino acid residues, one sulfhydryl group and 17 disulfide bridges. Among nanoparticulate carriers, HSA nanoparticles have long been the center of attention in the pharmaceutical industry due to their ability to bind to various drug molecules, great stability during storage and in vivo usage, no toxicity and antigenicity, biodegradability, reproducibility, scale up of the production process and a better control over release properties. In addition, significant amounts of drug can be incorporated into the particle matrix because of the large number of drug binding sites on the albumin molecule.[10]

• Maintains oncotic pressure
• Transports thyroid hormones
• Transports other hormones, in particular, ones that are fat-soluble
• Transports fatty acids ("free" fatty acids) to the liver and to myocytes for utilization of energy
• Transports unconjugated bilirubin
• Transports many drugs; serum albumin levels can affect the half-life of drugs. Competition between drugs for albumin binding sites may cause drug interaction by increasing the free fraction of one of the drugs, thereby affecting potency.
• Competitively binds calcium ions (Ca²⁺)
• Serum albumin, as a negative acute-phase protein, is down-regulated in inflammatory states. As such, it is not a valid marker of nutritional status; rather, it is a marker of an inflammatory state
• Prevents photodegradation of folic acid
• Prevent pathogenic effects of Clostridium difficile toxins[11]

Serum albumin is commonly measured by recording the change in absorbance upon binding to a dye such as bromocresol green or bromocresol purple.[12]

The normal range of human serum albumin in adults (> 3 y.o.) is 3.5–5.0  g/dL (35–50 g/L). For children less than three years of age, the normal range is broader, 2.9–5.5 g/dL.[13]

Low albumin (hypoalbuminemia) may be caused by liver disease, nephrotic syndrome, burns, protein-losing enteropathy, malabsorption, malnutrition, late pregnancy, artefact, genetic variations and malignancy.

High albumin (hyperalbuminemia) is almost always caused by dehydration. In some cases of retinol (Vitamin A) deficiency, the albumin level can be elevated to high-normal values (e.g., 4.9 g/dL). This is because retinol causes cells to swell with water (this is also the reason too much Vitamin A is toxic).[14] This swelling also likely occurs during treatment with 13-cis retinoic acid (isotretnoin), a pharmaceutical for treating severe acne, amongst other conditions. In lab experiments it has been shown that all-trans retinoic acid down regulates human albumin production.[15]

It has been known for a long time that human blood proteins like hemoglobin[25] and serum albumin[26][27] may undergo a slow non-enzymatic glycation, mainly by formation of a Schiff base between ε-amino groups of lysine (and sometimes arginine) residues and glucose molecules in blood (Maillard reaction). This reaction can be inhibited in the presence of antioxidant agents.[28] Although this reaction may happen normally,[26] elevated glycoalbumin is observed in diabetes mellitus.[27]

Glycation has the potential to alter the biological structure and function of the serum albumin protein.[29][30][31][32]

Moreover, the glycation can result in the formation of Advanced Glycation End-Products (AGE), which result in abnormal biological effects. Accumulation of AGEs leads to tissue damage via alteration of the structures and functions of tissue proteins, stimulation of cellular responses, through receptors specific for AGE-proteins, and generation of reactive oxygen intermediates. AGEs also react with DNA, thus causing mutations and DNA transposition. Thermal processing of proteins and carbohydrates brings major changes in allergenicity. AGEs are antigenic and represent many of the important neoantigens found in cooked or stored foods.[33] They also interfere with the normal product of nitric oxide in cells.[34]

Although there are several lysine and arginine residues in the serum albumin structure, very few of them can take part in the glycation reaction.[27][35]

The albumin is the predominant protein in most body fluids, its Cys34 represents the largest fraction of free thiols within body. The albumin Cys34 thiol exists in both reduced and oxidized forms.[36] In plasma of healthy young adults, 70–80% of total HSA contains the free sulfhydryl group of Cys34 in a reduced form or mercaptoalbumin (HSA-SH).[37] However, in pathological states characterized by oxidative stress and during the aging process, the oxidized form, or non-mercaptoalbumin (HNA), could predominate.[38] The albumin thiol reacts with radical hydroxyl (.OH), hydrogen peroxide (H₂O₂) and the reactive nitrogen species as peroxynitrite (ONOO.), and have been shown to oxidize Cys34 to sulfenic acid derivate (HSA-SOH), it can be recycled to mercapto-albumin; however at high concentrations of reactive species leads to the irreversible oxidation to sulfinic (HSA-SO2H) or sulfonic acid (HSA-SO3H) affecting its structure.[39] Presence of reactive oxygen species (ROS), can induce irreversible structural damage and alter protein activities.

In the healthy kidney, albumin's size and negative electric charge exclude it from excretion in the glomerulus. This is not always the case, as in some diseases including diabetic nephropathy, which can sometimes be a complication of uncontrolled or of longer term diabetes in which proteins can cross the glomerulus. The lost albumin can be detected by a simple urine test.[40] Depending on the amount of albumin lost, a patient may have normal renal function, microalbuminuria, or albuminuria.

Human serum albumin has been shown to interact with FCGRT.[41]

It might also interact with a yet-unidentified albondin (gp60), a certain pair of gp18/gp30, and some other proteins like osteonectin, hnRNPs, calreticulin, cubilin, and megalin.[42]

• Bovine serum albumin
• Serum albumin

• Human Albumin structure in the Protein data bank
• Human Albumin information in the Swis-Prot/TrEMBL database
• Human Serum Albumin on the Human Protein Reference Database
• Albumin binding prediction
• Albumin at Lab Tests Online
• Albumin: analyte monograph from the Association for Clinical Biochemistry and Laboratory Medicine
• Overview of all the structural information available in the PDB for UniProt: P02768 (Serum albumin) at the PDBe-KB.