IngredientsPhycocyanin (PC) is a protein from the phycobiliprotein family characterized by its intense blue color; its structure consists of a protein component and a non-protein component known as phycocyanobilin. More precisely, phycocyanobilin chromophore is an open-chain tetrapyrrole that is responsible for the deep blue tone of phycocyanin. The chromophore known as phycocyanobilin makes phycocyanin blue; it is an open-chain tetrapyrrole structure attached to apoproteins by thioether bonds.
The most commercially significant form is C-phycocyanin (C-PC), named according to the spectroscopic classification of phycobiliproteins in cyanobacteria. Phycocyanin is a blue-red fluorescent, water-soluble, and non-toxic biliprotein pigment. Unlike carotenoids, phycocyanin cannot exist within membranes because it is water-soluble. Phycocyanin shows fluorescence emission at around 650 nm and displays a discernible hue of light blue; depending on the kind, it absorbs red and orange light at 620 nm.
The polypeptide chain of phycocyanin constitutes α and β subunits forming heterodimeric monomers (αβ) by intermolecular interactions. Each monomer links to three chromophores by thioether linkage. The monomers polymerize naturally into trimers (αβ)3 and hexamers (αβ)6 to form phycocyanin.
C-phycocyanin (C-PC), a phycobiliprotein, is one of the key pigments of Spirulina, a microalgae used in many countries as a dietary supplement. The principal production organism is Arthrospira platensis (also referred to as Spirulina platensis). Arthrospira is a well-known type of blue-green algae, frequently used as a food supplement. It is a multicellular, filamentous, and photosynthetic cyanobacterium whose life cycle comprises several stages, including trichome fragmentation, hormogonia cell enlargement and maturation, and trichome elongation. The mature trichomes divide into filaments (2–16 μm) or hormogonia cells of different sizes, which reproduce by binary fission and take a helical or spiral shape.
The pigments of Spirulina platensis primarily originate from the light-harvesting protein complex named phycobiliprotein, which consists of phycocyanin, phycoerythrin, and allophycocyanin. Phycocyanin is the major constituent, while allophycocyanin functions as the bridging pigment between phycobilisomes and the photosynthetic lamella. Spirulina possesses approximately 25% w/w of phycocyanin in its total biomass. Beyond Spirulina, phycocyanin is a light-harvesting pigment and nitrogen-storing protein found in prokaryotic cyanobacteria species, as well as in eukaryotic microalgae.
Phycocyanin from a Spirulina extract is, to date, the only natural blue pigment approved by the US FDA and European Union as a coloring food. It is sold in liquid or powder form for use as a blue pigment in foods. In the nutraceutical, pharmaceutical, and cosmeceutical industries, phycocyanin is used at higher purities for its anti-oxidant and anti-inflammatory properties, together with other associated health benefits. At its highest quality and purity, phycocyanin is used in laboratory assay kits for its fluorescent properties.
Purity is a critical parameter in commercial phycocyanin preparations. The "purity index" (PI) is determined by the ratio of absorbance at 620 nm to absorbance at 280 nm: a PI of 0.7 is considered food-grade, a PI above 3.9 is considered reagent-grade, and a PI above 4.0 is considered analytically pure. Current methods for extracting and purifying phycocyanin from a biomass include vacuum distillation, ammonium sulfate precipitation, ultrafiltration, adsorption, and various chromatographic purification methods.
The biggest challenges to the widespread application of phycocyanin are its high sensitivity to chemical degradation when exposed to heat, light, acids, high pressure, heavy metal cations, and denaturants. Phycocyanin has the disadvantage of being unstable in aqueous systems between pH 2.7–6, where protein aggregation occurs, and is also unstable under thermal treatment, leading to loss of color.
Phycocyanin was not isolated or named as a distinct compound until the modern era; however, its primary source — Arthrospira/Spirulina — has a well-documented history of human consumption spanning several centuries, with phycocyanin comprising a substantial fraction of its bioactive content.
Spirulina, also known as Arthrospira, is a type of blue-green algae that has been consumed by humans for centuries. Historical records reveal its use as a food source by the Aztecs and other Mesoamerican cultures dating back to the 16th century. The Aztecs and other Mesoamericans used it as a food source in Mexico. As described by one of Hernán Cortés' soldiers, algae were harvested at Lake Texcoco and turned into cakes called tecuitlatl. Traditionally, it was harvested from the alkaline waters of Lake Texcoco in Mexico and transformed into dried cakes for consumption.
Historically, spirulina has been used as food by the Kanembu ethnic group in the Lake Chad region of the Republic of Chad, to make and sell dried bread called dihé. After being rediscovered by a European scientific mission in Chad, this traditional food gained popularity in the human health food industry around the world. For the Kanembu people, spirulina has long been a vital dietary component. It is harvested manually and sun-dried into cakes for storage and later consumption, a simple yet effective method that ensured food security during harsh conditions.
The Aztecs harvested spirulina from Lake Texcoco, drying it into cakes they called tecuitlatl, while the Kanembu people sun-dried it into flat disks called dihé. Whether it was used as medicine, per se, is hard to pin down, as historical documentation is patchy. Most of what is known about traditional use is anthropological rather than clinical. There is no solid evidence for specific therapeutic use in ancient cultures — the record suggests the material was nutritious and made people feel better, which could represent protein supplementation rather than targeted medicinal application.
The term "phycocyanin" is modern; ancient consumers were ingesting the whole algal biomass, of which phycocyanin was one constituent. This algae species is abundant in high-quality plant proteins, polysaccharides, carotenoids, phycocyanin, vitamins, minerals, and other trace elements. The deliberate isolation and therapeutic application of phycocyanin as a discrete compound is entirely a product of twentieth- and twenty-first-century science.
The structure of phycocyanin comprises a protein part and a non-protein chromophore part called phycocyanobilin. The phycocyanobilin chromophore is structurally related to bilirubin and biliverdin — open-chain tetrapyrroles that are endogenous antioxidants in mammals — and this structural kinship is considered the molecular basis for many of phycocyanin's free-radical-scavenging properties. The biliprotein nature of phycocyanin, combining the chromophore's direct radical-quenching activity with the protein scaffold's enzymatic-inhibitory capacity, distinguishes it mechanistically from simple polyphenolic antioxidants.
All phycobiliproteins absorb incident light directly, but in addition they participate in an energy transfer chain within the phycobilisome in a sequence: phycoerythrin → phycocyanin → allophycocyanin → chlorophyll-a. The phycobiliproteins were introduced as a novel class of fluorescent dyes in 1982. These naturally occurring fluorescent phycobiliproteins were used immediately in diagnostic assays and in diverse research applications. The phycobiliproteins serve as valuable fluorescent tags with numerous applications in flow cytometry, fluorescence-activated cell sorting, histochemistry, and to a limited degree in immunoassay and detection of reactive oxygen species.
When evaluated as an antioxidant in vitro, phycocyanin was able to scavenge alkoxyl, hydroxyl, and peroxyl radicals and to react with peroxynitrite (ONOO−) and hypochlorous acid (HOCl). It also inhibits microsomal lipid peroxidation induced by Fe2+-ascorbic acid or the free radical initiator AAPH. Furthermore, it reduces carbon tetrachloride (CCl4)-induced lipid peroxidation in vivo.
Oxidative stress and inflammation were curtailed by affecting three main pathways: (1) inhibition of cyclooxygenase-2 enzyme and consequent decrease of signaling generating reactive oxygen species; (2) increased synthesis of glutathione and therefore strengthening of the natural antioxidant defenses of the cells; (3) decreased infection-driven mitochondrial respiratory burst which generates oxidative stress.
The bright blue light-harvesting pigment phycocyanin, unique to cyanobacteria, is a known antioxidant and anti-inflammatory compound, in part due to its ability to inhibit the inflammatory enzyme cyclooxygenase-2 (COX-2). In the human whole blood assay, phycocyanin very efficiently inhibited COX-2 with an IC50 value of 80 nM. Reduced phycocyanin and phycocyanobilin, the chromophore of phycocyanin, are poor inhibitors of COX-2 without COX-2 selectivity. This suggests that the apoprotein in phycocyanin plays a key role in the selective inhibition of COX-2.
Based on experimental results, the inhibition of nitric oxide and prostaglandin E2 over-production through suppressing iNOS and COX-2 induction, and attenuation of TNF-α formation and neutrophil infiltration into inflammatory sites by C-PC, may contribute to its antihyperalgesic and anti-inflammatory activity. The anti-inflammatory activity of C-PC, partly through inhibition of proinflammatory cytokine formation, inducible nitric oxide synthase (iNOS), and COX-2 expression, has been demonstrated in many in vitro and in vivo studies.
The anti-inflammatory effects of phycocyanin can be attributed to its scavenging properties toward reactive oxygen species and its inhibitory effects on COX-2 activity and on histamine release from mast cells. Phycocyanin also reduced the levels of tumor necrosis factor (TNF-α) in the blood serum of mice treated with endotoxin, and showed neuroprotective effects in rat cerebellar granule cell cultures and in kainate-induced brain injury in rats.
In addition to promoting the downregulation of NF-κB, C-PC derived from Limnospira platensis showed potent inhibition of COX-2. The hepatoprotective, anti-inflammatory, and anti-arthritic properties of phycocyanin reported in the literature may be due, in part, to its selective COX-2 inhibitory property, although its ability to efficiently scavenge free radicals and effectively inhibit lipid peroxidation may also be involved.
C-phycocyanin (C-PC) is one of the major biliproteins of Spirulina platensis, a blue-green alga, with antioxidant and radical-scavenging properties. It is also known to exhibit anti-inflammatory and anti-cancer properties. However, the mechanism of action of C-PC is not clearly understood. C-PC has been shown to selectively inhibit COX-2, an inducible isoform that is upregulated during inflammation and cancer. C-PC-induced apoptosis in LPS-stimulated RAW 264.7 macrophage cells appears to be mediated by the release of cytochrome c from mitochondria and is independent of Bcl-2 expression. These effects appear to be due to reduced prostaglandin E2 (PGE2) levels as a result of COX-2 inhibition.
Phycocyanin exerts anti-cancer activity by blocking tumor cell cell-cycle, inducing tumor cell apoptosis and autophagy, thereby serving as a promising anti-cancer agent. When C-PC treated tumor cells HT-29 and A549, the cell cycle was blocked in the G0/G1 phase, DNA synthesis was blocked, and thus tumor cell proliferation was inhibited. Evidence exists supporting that phycocyanin has antitumor effects, exerting its pharmacological effects by targeting a variety of cellular and molecular processes, i.e., apoptosis, cell-cycle arrest, migration, and Wnt/β-catenin signaling.
Phycocyanin scavenges free radicals from damaged nerve cells, which could avoid DNA oxidative damage caused by free radicals and prevent neuronal cell apoptosis. Phycocyanin is reported to have potent therapeutic properties including neuroprotective effects, which are principally attributed to its strong antioxidant activity.
Phycocyanin plays an antioxidant role in inhibiting hepatic lipid peroxidation and is helpful for liver protection. Antioxidant, anti-inflammatory, neuroprotective, and hepatoprotective effects have been experimentally attributed to phycocyanin.
Phycocyanin has been evaluated in twelve experimental models of inflammation and exerted anti-inflammatory effects in a dose-dependent fashion in all of these. The antioxidant capacity of C-PC has been characterized extensively in preclinical studies. Food-grade phycocyanin isolated from Spirulina platensis has been evaluated for its in vitro and in vivo antioxidant potential using a battery of antioxidant assays including DPPH, TAC, FRAP, hydroxyl radical, hydrogen peroxide scavenging, SOD, GSH, and lipid peroxidation (LPO) assays.
In terms of human evidence, adults with metabolic syndrome who consumed a spirulina liquid extract rich in phycocyanin (about 20 mg phycocyanin per day) for 12 weeks showed improvements in triglycerides, HDL cholesterol, and urinary isoprostanes compared with placebo. Liver safety markers remained stable, and no serious adverse events were reported. Urinary isoprostanes are an established biomarker of systemic oxidative stress, and this finding represents one of the few human studies providing direct evidence of an antioxidant effect attributable primarily to the phycocyanin fraction. The overall body of human-level antioxidant evidence remains limited and preliminary.
Pre-clinical evidence from multiple animal models is robust. Phycocyanin has been evaluated in twelve experimental models of inflammation and exerted anti-inflammatory effects in a dose-dependent fashion in all of these. In vivo studies demonstrate phycocyanin's efficacy in reducing TNF-α levels and neutrophil infiltration in inflammation models.
In human studies, previous pilot studies on a phycocyanin-rich aqueous cyanophyta extract (ACE) showed that consumption at a dose of 0.25–1.0 g/day was associated with relief of chronic pain. These pilot data are preliminary and require confirmation in larger, adequately-powered randomized controlled trials (RCTs). No large-scale RCT has, as of the available literature, been conducted specifically on phycocyanin as an isolated anti-inflammatory agent in humans.
Phycocyanin and phycocyanobilin have the potential to avoid endothelial dysfunction due to their antioxidant and anti-inflammatory properties, and signaling pathway modulation on NADPH oxidase and COX-2. The antihypertensive action of C-phycocyanin is related to the prevention of angiotensin II-caused vascular dysfunction in chronic kidney disease.
A body of evidence from spirulina supplementation trials (using whole spirulina biomass at 1–19 g per day) reports improvements in blood lipids — including total cholesterol, LDL-cholesterol, triglycerides, and HDL-cholesterol — and in blood pressure. Attribution of these effects specifically to the phycocyanin fraction, rather than to other spirulina constituents such as gamma-linolenic acid, phytonutrients, and complete protein, has not been definitively established in human trials. Evidence at the level of isolated phycocyanin in cardiometabolic outcomes in humans is preliminary.
There are increasing reports showing that phycocyanin plays an effective anti-cancer role in various cancer cell types such as breast cancer, liver cancer, lung cancer, colon cancer, leukemia, and bone marrow cancer in vitro and in vivo. The molecular mechanism of action of C-PC for its anticancer activity could be the blockage of cell cycle progression, inducing apoptosis and autophagy in cancer cells. Data from various studies suggest therapeutic applications including anti-cancer activity, anti-inflammation, anti-angiogenic activity, and healing capacity in certain autoimmune disorders.
In vitro and in vivo data on the effects of phycocyanin on various tumor cells and on cells from healthy tissues have been summarized in published reviews. However, as of available literature, no completed Phase II or Phase III randomized clinical trials demonstrating clinical efficacy of isolated phycocyanin against cancer in human populations have been published. A clinical trial hypothesis has been proposed that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastrointestinal cancers including oesogastric, colorectal, and pancreatic cancers, and this has been registered as a randomized, placebo-controlled study. Anticancer evidence for phycocyanin in humans remains, as of the published record, entirely preliminary.
Phycocyanin has been applied in treatment of several gastrointestinal disorders such as gastric ulcer, ulcerative colitis, and fatty liver, the latter being a known risk factor for progression to cancer. The experimental evidence for these effects is predominantly from cell-based and animal models. Human-level clinical evidence targeting phycocyanin specifically for gastrointestinal indications is limited.
Phycocyanin plays an antioxidant role in inhibiting hepatic lipid peroxidation and is considered helpful for liver protection. In the human double-blind study on phycocyanin-enriched extract, serum levels of aspartate transaminase (AST) showed a significant reduction after 2 weeks of ACE consumption (P < 0.001), in contrast to placebo where no changes were seen. This is one of the few human-trial findings for a hepatoprotective signal from phycocyanin, though the study was short (2 weeks), small (N=24), and the ACE extract is not pure phycocyanin.
Phycocyanin, a member of the phycobiliprotein family, is considered a neuroprotective compound based on available experimental data. The neuroprotective evidence derives primarily from rodent models, including kainate-induced brain injury and cerebellar granule cell culture models. Human clinical data on phycocyanin for neuroprotection are absent from the current published literature. Evidence remains preclinical.
Earlier in vitro studies have shown that C-phycocyanin has many biological activities including antioxidant and anti-inflammatory activities, antiplatelet, hepatoprotective, and cholesterol-lowering properties. Results of in vivo evaluation suggest that C-phycocyanin is very safe for consumption and has substantial antioxidant potential and also possesses immunomodulatory activities in Balb/c mice in a dosage-dependent manner. Human clinical data on immunomodulatory endpoints for isolated phycocyanin are sparse.
Naturally occurring fluorescent phycobiliproteins were used immediately upon their characterization in 1982 in diagnostic assays and in diverse research applications. The phycobiliproteins serve as valuable fluorescent tags with numerous applications in flow cytometry, fluorescence-activated cell sorting, histochemistry, and to a limited degree in immunoassay and detection of reactive oxygen species. This is a well-established, non-dietary application of phycocyanin in biomedical research and diagnostics.
Phycocyanin is commercially available in the following forms:
It should be noted that the above dosages derive from varied study designs and populations. No pharmacopeial standardized dosage for phycocyanin as a drug or supplement has been established by a regulatory body, and dose selection in published studies spans a wide range.
Dried biomass products of Arthrospira and Chlorella have been categorized as "generally recognized as safe" (GRAS) by the US Food and Drug Administration (FDA). Phycocyanin has relatively recently been approved as a food additive in both the USA, where it is exempt from certification, and by the EU, where it does not require an E-number. Spirulina-derived phycocyanin provides the only natural blue dye approved in the United States and Asia, although reports vary regarding its current EU status as a coloring food. Initially, phycocyanins were used only to color sweets and chewing gums, but innovations in food processing have allowed the range of phycocyanin-colored products to be extended to dairy products, soft drinks, and cosmetics.
C-phycocyanin has a wide margin of safety; there was no mortality or behavioral changes at a dose of 2000 mg/kg in animal studies, and no obvious toxic symptoms were observed throughout the study period. No significant deviations were found in body weight between control and C-phycocyanin-treated mice after 30 days of sub-acute toxicity study. The C-PC-treated mice did not show any signs and symptoms of toxicity. Clinical and biochemical parameters as well as histopathological evaluations of the kidney and liver revealed normal status.
In vivo toxicology studies of Arthrospira platensis have not revealed any toxic effects on the kidney.
Because phycocyanin is a selective COX-2 inhibitor with structural properties that overlap with anti-platelet drugs, its safety profile regarding blood coagulation was specifically studied. Consuming the ACE extract did not alter markers for platelet activation (P-selectin expression) or serum P-selectin levels. No changes were seen for activated partial thromboplastin time, thrombin clotting time, or fibrinogen activity. This finding, from a prospectively designed RCT using approximately 1 g phycocyanin/day over 2 weeks, indicates that at this dose, phycocyanin does not measurably affect the coagulation cascade in healthy adults. The study was, however, limited to 2 weeks and a sample size of 24.
Serum levels of aspartate transaminase (AST) showed a significant reduction after 2 weeks of ACE consumption (P < 0.001), in contrast to placebo where no changes were seen. This finding, while suggesting a hepatoprotective rather than hepatotoxic signal, was unexpected and its clinical significance in healthy subjects requires further investigation.
The biggest challenges to phycocyanin's widespread application are its high sensitivity to chemical degradation when exposed to heat, light, acids, high pressure, heavy metal cations, and denaturants. Because phycocyanin is derived from cyanobacteria, a recognized concern in the field is the potential for co-contamination with cyanotoxins, particularly microcystins, in lower-quality preparations. High-quality commercial products use purification steps specifically designed to remove these compounds.
Phycocyanin is a non-toxic photosensitizer that can be used as an adjuvant in the photodynamic therapy (PDT) of tumors. This photosensitizer property, while exploited in research settings, is a relevant characteristic when considering topical or systemic applications involving light exposure.
Persons with liver, kidney, autoimmune, or bleeding disorders represent groups where a more cautious approach and professional oversight are warranted. The interaction of phycocyanin with immunosuppressive drugs (given its immunomodulatory properties) and with anticoagulant or antiplatelet medications (given its COX-2 inhibitory activity and early laboratory data suggesting platelet effects) has not been characterized in dedicated pharmacokinetic interaction studies in humans.
The following table summarizes the evidence strength for each major application area as derived from the published literature:
Health conditions that Phycocyanin may help support.
Body systems that Phycocyanin may help support.
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