Clinical potential of spirulina as a source of phycocyanobilin

JOURNAL OF MEDICINAL FOOD
J Med Food 10 (4) 2007, 566–570
Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2007.621
Perspective
Clinical Potential of Spirulina as a Source of Phycocyanobilin
NutriGuard Research, Encinitas, California Recent research reveals that free bilirubin functions physiologically as a potent inhibitor of NADPH oxidase activity. The chromophore phycocyanobilin (PCB), found in blue-green algae and cyanobacteria such as Spirulina, also hasbeen found to be a potent inhibitor of this enzyme complex, likely because in mammalian cells it is rapidly reduced to phy-cocyanorubin, a close homolog of bilirubin. In light of the protean roles of NADPH oxidase activation in pathology, it thusappears likely that PCB supplementation may have versatile potential in prevention and therapy—particularly in light of ro-dent studies demonstrating that orally administered Spirulina or phycocyanin (the Spirulina holoprotein that contains PCB)can exert a wide range of anti-inflammatory effects. Until PCB-enriched Spirulina extracts or synthetically produced PCB arecommercially available, the most feasible and least expensive way to administer PCB is by ingestion of whole Spirulina. Aheaping tablespoon (about 15 g) of Spirulina can be expected to provide about 100 mg of PCB. By extrapolating from rodentstudies, it can be concluded that an intake of 2 heaping tablespoons daily would be likely to have important antioxidant ac-tivity in humans—assuming that humans and rodents digest and absorb Spirulina-bound PCB in a comparable manner. Anintake of this magnitude can be clinically feasible if Spirulina is incorporated into “smoothies” featuring such ingredients assoy milk, fruit juices, and whole fruits. Such a regimen should be evaluated in clinical syndromes characterized and in partmediated by NADPH oxidase overactivity in affected tissues.
KEY WORDS: • antioxidant • bilirubin • biliverdin • heme oxygenase • inflammation • NADPH oxidase •
phycocyanin • phycocyanobilin • Spirulina • zeaxanthin
NADPH OXIDASE AS A MEDIATOR
to cancer initiation, boosts growth factor activity in some OF PATHOLOGY
cancers, and is a mediator of the angiogenic process. Thus,it is reasonable to suspect that tolerable clinical strategies IN A HIGH PROPORTION of non-infectious pathologies, for down-regulating NADPH oxidase activity may have a
NADPH oxidase becomes activated in the affected tis- remarkably versatile potential in both preventive and thera- sues, and the resulting generation of oxidants either medi- peutic medicine. Indeed, the surprising range of benefits as- ates or exacerbates the pathology. Thus, as cited earlier,1 sociated with statin and angiotensin converting enzyme in- overactivity of this enzyme complex appears to play a role hibitor therapies likely reflects, in part, their ability to in a host of vascular disorders, including atherogenesis, hy- suppress NADPH oxidase activation in certain tissues.2,3 pertension, left ventricular hypertrophy, aneurysms, and Fortunately, Nature has equipped us with feedback mech- ischemia-reperfusion injury; the insulin resistance associ- anisms that help to moderate the generation of oxidant stress.
ated with obesity; the major complications of diabetes; neu- In particular, recent research has established that free biliru- rodegenerative disorders such as Alzheimer’s and Parkin- bin, in the low nanomolar concentrations that prevail intra- son’s diseases; various autoimmune conditions, including cellularly, functions physiologically as a potent and highly Downloaded by California Digital Library (CDL) from www.liebertonline.com at 12/25/07. For personal use only.
rheumatoid arthritis and scleroderma; allergy and asthma; specific inhibitor of NADPH oxidase.4–6 Intracellular oxi- hepatic fibrosis; ultraviolet-mediated skin damage; and the dant stress induces expression of heme oxygenase-1, which cartilage loss associated with osteoarthritis. Oxidant stress in turn generates bilirubin from heme via biliverdin7,8; this generated by NADPH oxidase also sometimes contributes mechanism provides feedback control of the oxidant stressmediated by NADPH oxidase. Bilirubin’s suppressive im- Manuscript received 20 June 2007. Revision accepted 4 August 2007.
pact on NADPH oxidase activity likely explains the grow-ing epidemiological literature that associates increased Address reprint requests to: Mark F. McCarty, NutriGuard Research, 1051 Hermes Av-enue, Encinitas, CA 92024, E-mail: mccarty@pantox.com serum bilirubin, or high-expression polymorphisms of heme SPIRULINA AS PHYCOCYANOBILIN SOURCE oxygenase-1, with diminished risk for vascular disorders, monly employed compromise between these two standards certain cancers, and various other diseases.1,9–12 is to adjust dose by the 3/4 power of the ratio of bodyweights; this has been found to offer a “best fit” when ex- PHYCOCYANOBILIN (PCB)—A
trapolating various quantifiable metabolic parameters be- PHYTONUTRIENT INHIBITOR OF
tween mammalian species.30–32 The 3/4 power standardyields a correction factor of about 80 if comparing a 200 g NADPH OXIDASE
rat with a 70 kg human, or a factor of 450 if comparing a Potentially, bilirubin, or preferably its more soluble pre- 20 g mouse with a 70 kg human. (In other words, if a rat cursor biliverdin, could be used as orally administered an- receives x mg of an agent, the corresponding human dose tioxidants for prevention and control of a wide range of dis- orders. However, there are no rich natural sources of these In an extensive series of investigations, Romay and co- compounds, which moreover are difficult and expensive to workers have reported that oral phycocyanin administered synthesize. It is therefore quite fortunate that many algae orally to mice and rats exerts a number of dose-dependent and cyanobacteria are rich in the compound PCB, a chro- anti-inflammatory effects in a dose range of 50–300 mophore that, as a component of the holoprotein phyco- mg/kg/day.15–18 This amounts to a PCB intake of 2.35–14.1 cyanin, aids the harvesting of light energy.13 PCB is a mg/kg. If extrapolated on a mg/kg basis, this corresponds to biliverdin derivative that, in mammalian cells, is converted a daily intake of 165–990 mg in a 70 kg human. Extrapo- by the ubiquitously expressed enzyme biliverdin reductase lation by the 3/4 power standard gives human daily intakes to phycocyanorubin, a compound nearly identical in struc- of 21.2–127 mg (using mice) and 37.6–226 mg (using rats).
ture to bilirubin.14 Recent studies by T. Inoguchi (personal Recent studies in which whole Spirulina has been ad- communication) show that addition of either PCB or its ho- ministered orally to rodents have also shown anti-inflam- molog biliverdin to human cell cultures leads to potent in- matory effects, in doses ranging from 150 to 1,000 hibition of NADPH oxidase; this effect is dose-dependent mg/kg/day.19–24 This amounts to intakes of 1–6.6 mg/kg/day in the low micromolar range, and near maximal at 20 ␮M.
PCB. Extrapolating on the basis of relative weight, this cor- The fact that orally administered phycocyanin or Spirulina responds to an intake of 70–462 mg PCB in a 70 kg human.
exerts potent and versatile anti-inflammatory effects in ro- Extrapolating on the basis of the 3/4 power standard, it cor- dents15–24 strongly suggests that ingested PCB can be suf- responds to an intake of 9–59 mg (mouse studies) or 16–106 ficiently well absorbed to provide important systemic an- mg (rat studies). The syndromes in which Spirulina demon- tioxidant activity. PCB’s homolog biliverdin is likewise strated protective efficacy included adjuvant arthritis, effective when administered orally.25–27 Thus, PCB supple- MPTP-induced parkinsonism, doxorubicin-induced car- ments, once available, may have considerable potential for diomyopathy, and nephropathy mediated by cisplatin and cyclosporine; it is unlikely to be coincidental that activation However, until PCB-enriched Spirulina extracts or PCB of NADPH oxidase has been shown to be a key mediator of derived from bioengineered organisms28 or chemical syn- thesis are commercially available, the most practical source As noted, a heaping tablespoon of Spirulina contains ap- of PCB for supplemental use is whole Spirulina. Phyco- proximately 100 mg of PCB. Thus, a regimen of 2 heaping cyanin constitutes about 14% of the total dry weight of Spir- tablespoons per day—arguably the highest intake that would ulina; PCB represents about 4.7% of the mass of phyco- be feasible on a long-term basis with well-motivated pa- cyanin.29 It follows that about 0.66% of the dry mass of tients—would provide about 200 mg of PCB daily. This in- Spirulina is PCB. In other words, 15 g of Spirulina—ap- take is thus within—and in some instances a bit beyond— proximately a heaping tablespoon—contains about 100 mg the extrapolated dose ranges noted above. It should follow of PCB. The fraction of this that is absorbed in a form ca- that—assuming that humans digest and metabolize Spir- pable of inhibiting NADPH oxidase is unknown.
ulina-bound PCB much like rodents do—a daily intake of2 heaping tablespoons of Spirulina daily should have clini- SPIRULINA AS PRACTICAL CLINICAL
cally useful antioxidant activity in humans. Thus, it wouldbe reasonable to test such a regimen in the prevention or SOURCE OF PCB
treatment of the wide range of clinical disorders in which If we make the not unreasonable assumption that ab- overactivity of NADPH oxidase plays a pathogenic role. As- sorption and metabolism of Spirulina-bound PCB are simi- sessing impact on clinical hypertension might be a good Downloaded by California Digital Library (CDL) from www.liebertonline.com at 12/25/07. For personal use only. lar in rodents and humans, then clinically useful dose regi- place to start, since an effective dose regimen could be ex- mens of Spirulina can be estimated by extrapolating from pected to have a rapid and quantifiable impact.45–51 In this regimens that demonstrate antioxidant efficacy in rodents.
regard, it is pertinent to note that, in a cohort of 50 middle- Such dose extrapolation can be done straightforwardly on a aged Czech subjects with Gilbert’s syndrome (average age mg/kg basis. However, in clinical practice, dose is often ad- 50 years), only one was found to be hypertensive.9 Intrigu- justed by relative body surface area, which corresponds to ingly, Remirez et al.20 stated that “a number of published the 2/3 power of the ratio of body weights. This latter stan- reports suggest beneficial effects of this microalgae in hy- dard evidently yields a much lower correction factor. A com- pertension . . .”—without, however, citing these reports.
Ultimately, the availability of PCB supplements—ex- type 2 diabetics62; it is not clear what mediates this effect tracted from Spirulina or synthesized—should enable a (soluble fiber?), or whether this effect (if real) might be of broader assessment of the dose dependency of PCB’s clin- a greater and more clinically significant magnitude with the ical benefits. Such supplements will improve the conve- higher doses of Spirulina recommended here.
nience of PCB ingestion, and make it possible to achieve It must be borne in mind, of course, that complete inhi- PCB intakes greater than those feasible with whole Spir- bition of NADPH oxidase would be inappropriate and dan- ulina. Nonetheless, until PCB can be mass-produced inex- gerous, particularly in light of the key role which NADPH pensively via chemical synthesis or bioengineered bacteria, oxidase plays in phagocyte bactericidal mechanisms and in ingestion of whole Spirulina will be the least expensive way T cell regulation.63,64 Fortunately, people with Gilbert’s syn- to benefit from this phytonutrient. It should be noted that drome, characterized by chronic moderate (two- to three- the relative absorption and bioefficacy of free PCB and Spir- fold) up-regulation of free bilirubin levels, have not been ulina-bound PCB have not yet been assessed, in either ro- noted to be especially prone to infection—even though they dents or humans; evidently, this issue requires attention.
are at reduced risk for vascular disorders. This suggests that Among health food devotees, Spirulina is frequently in- moderate, partial inhibition of NAPDH oxidase can be as- gested in “smoothies”; a smoothie made by blending a cup sociated with worthwhile health benefits without entailing of vanilla soy milk, one banana, and a heaping tablespoon an important compromise of immune defenses—perhaps in of Spirulina is reasonably palatable (albeit it looks like part because phagocytes have recourse to ancillary bacteri- frothy green slime!), and provides in addition soy cidal mechanisms.65 In any case, once PCB supplements are isoflavones and an ample amount of potassium (about 1 g).
available, their use could be temporarily discontinued when Various fruit juices and whole fruits can also be used to pro- persistent or life-threatening infections develop. The impact duce Spirulina smoothies; for example, cinnamon-spiced ap- of whole Spirulina on infection may be complex, since, as ple juice works very well. The flavor of Spirulina, although noted, the cell wall polysaccharides of Spirulina can act as unappealing to most people, is relatively mild, and thus sus- ceptible to masking by a variety of flavors.
NOTE ADDED IN PROOF
SAFETY CONSIDERATIONS
Since the submission of this review, Riss et al.66 have re- AND ANCILLARY BENEFITS
ported that orally administered phycocyanin or whole Spir-ulina “powerfully prevents the development of atheroscle- With respect to safety considerations, it should be noted rosis” in cholesterol-fed hamsters. Although this appears to that Spirulina once was a staple of the Aztec diet, and ro- be the first published evidence that Spirulina has vascular- dents show no ill effects when fed diets in which Spirulina protective potential, it is consistent with the central role that constitutes 30% of total weight.52–54 Fifteen grams of Spir- NADPH oxidase plays in atherogenesis.
ulina provides about 70 mg of total carotenoids—carotenes(54%) and xanthophylls (46%); this may make an ancillarycontribution to the physiological antioxidant activity of this REFERENCES
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