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PHYTIC ACID (MYO-INOSITOL HEXAPHOSPHATE)- A PROMISING PHARMACEUTICAL AGENT: A REVIEW

Phytic acid (myo-inositol hexaphosphate) has gained much attention among researchers for its therapeutic value. This review focuses on pharmacological activities of phytic acid, which have been demonstrated by pre-clinical studies. Anti-carcinogenic, antioxidant, antidiabetic, hypolipidemic, anti-angiogenic, and immunomodulation are the most extensively studied pharmacological activities of phytic acid. In addition to these, phytic acid and its derivatives also possess enzyme inhibitory activities against few key enzymes such as 5-alpha reductase, aldose reductase, cyclooxygenase, lipase, matrix metalloproteinase-2 & 9, pepsin, polyphenol oxidase, protease, β-secretase, tyrosinase, and xanthine oxidase were emphasized. The profound pharmacological activities of phytic acid have proven to be a good therapeutic agent and could be employed in preventing as well as treating such diseases.


INTRODUCTION
Phytic acid is chemical known as myo-inositol hexaphosphate, which is abundant in nature and especially in plants it accounts for 1-5% weight of edible cereals, legumes, nuts, oil seeds, and tubers [1][2][3]. The process of synthesizing phytic acid is metabolically expensive, which requires six adenosine triphosphate molecules for phosphorylation of each phytic acid molecule [4]. An average intake of phytate by humans on vegetarian diets is about 2000-2600 mg/day [5]. It is readily absorbed in the gastrointestinal (GI) tract and then enters the bloodstream [6]. It is also physiologically present in the human large intestine [7].
Phytic acid is a unique negatively charged molecule in a wide pH range and having 12 replaceable protons in it [8]. These characteristic chemical natures allow the formation of metal complexes with polyvalent metals especially with divalent and trivalent [9]. Phytases are the only enzymes, which capable of hydrolyzing phytic acid into myo-inositol and inositol phosphates [1]. Phytic acid has been well known as anti-nutrient agent in the past. Recently, phytic acid has been extensively studied due to its numerous biological activities; therefore, it is worthwhile to review recent findings on phytic acid and its pharmacological activities. The present review, we describe the recent therapeutic potential of phytic acid as a promising pharmaceutical agent.

PHARMACOLOGICAL ACTIVITIES OF PHYTIC ACID
Few important pharmacological activities of phytic acid have been shown in Fig. 1 wherein, all these publications exemplify the numerous pharmaceutical studies and deliberately confirmed the potential therapeutic value of the phytic acid against various diseases. Furthermore, antineoplastic/anticarcinogenic activity of phytic acid has more number of studies/publications, which is followed by antioxidant activity and so on (Fig. 1).

Antibacterial activity of phytic acid
Phytic acid is the main storage form of phosphorus in many plant tissues. Recently, food-grade phosphate (including phytic acid) has gained importance among researchers, due to its usefulness as a food additive in a wide variety of meat products. A number of researchers have reported that phosphates shown to exhibit antimicrobial activities, although it has never been classified as an antimicrobial agent. Sodium phytate (sodium salt of phytic acid) has been reported to inhibit Escherichia coli growth in raw or cooked meats including beef, chicken, and pork [10]. In other study, phytic acid from rice bran has been reported to inhibit the growth of both Salmonella typhimurium and E. coli [11].

Antidiabetic activity of phytic acid
Yoon et al. [12] reported that phytate-enriched diets result in low blood glucose (glycemia) levels in humans. Later two reports shown that phytate regulates insulin secretion through inhibiting the serine/ threonine-specific protein phosphatase activity, which, in turn, opens intracellular calcium channels required for insulin release [13,14]. Kuppusamy et al. [15] reported that phytic acid has been shown to exhibit both α-glucosidase and α-amylase inhibition in dose-dependent manner (in vitro) and also shown to possess antidiabetic activity against streptozotocin-nicotinamide induced diabetes (type 2) in rats. In other study, phytic acid extracted from Kenyan local vegetables and grains have been shown to possess both α-glucosidase and α-amylase inhibition [16].

Anti-inflammatory activity of phytic acid
Recent investigations suggest that bioactive natural dietary products play a key role in the alleviation and control of inflammation-related diseases [17,18]. Phytic acid has been reported to exhibit antiinflammatory activity against carrageen induced paw edema in experimental rats [19].

Antiviral activity of phytic acid
Phytic acid has been reported to inhibit the proliferation of human immunodeficiency virus (HIV) under in vitro condition [38]. In other study, anti-HIV1 activity of both myo-inositol hexaphosporic acid (IP6) and myo-inositol hexasulfate (IS6) has been reported in detail [39].

Cariostatic activity of phytic acid
Sodium phytate (sodium salt of phytic acid) has been shown to possess cariostatic activity using in vivo studies [40][41][42]. Kaufman and Kleinberg [43] reported that the cariostatic action of phytic acid and its derivatives have been attributed mainly, due to its ability to lower solubilizes of calcium, fluoride, and phosphate as they major components of tooth enamel. Phytic acid has been tested in toothpaste as a tool for preventing tooth plaque formation [44].

Hemolytic activity of phytic acid
Hemolytic activity of any substances or compounds is a measure of general cytotoxicity toward normal healthy cells. Phytic acid has not shown any hemolysis at ≥1 mM concentration level, however significantly increases the percentage of annexin V-binding erythrocytes [45].

Hypoallergenic activity of phytic acid
Peanut allergy is one of the most common food allergies among the schoolchildren in United States of America (USA) and United Kingdom. Phytic acid has been shown to possess hypoallergenic activity against peanut allergens [46]. Katayama [47] reported the hypolipidemic activity of phytic acid in rat model. Lee et al. [48] reported that dietary phytic acid reduces serum and hepatic lipid levels in aged ICR mice feed with high cholesterol diet. In other study, phytic acid has been reported to possess antihyperlipidemic activity against high fat-induced mice model [49].

Immunomodulatory activity of phytic acid
An immunomodulatory agent is a substance that may be an immunostimulator or an immunosuppressant based on its effect on the immune system. Phytic acid has been shown to possess immunomodulatory activity against bacterial lipopolysaccharide-induced human mononuclear cells [50].

Neuroprotective activity of phytic acid
Alterations in antioxidant status in nervous tissue have been implicated in pathologies of neurodegenerative disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Phytic acid has been shown to possess neuroprotective activity against Parkinson's disease [51,52].

Phytic acid against renal stone formation
Renal stone disease is an ailment afflicting human beings for many centuries. A majority of renal stones are calcium stones, which account approximately 80% of all of these stones. Phytic acid has been reported to inhibit the calcium oxalate crystal formation, which, in turn, prevents renal stone formation [53,54].

ENZYME INHIBITORY ACTIVITIES OF PHYTIC ACID AND ITS DERIVATIVES
Few reported enzyme inhibitory activities of phytic acid and its derivatives have been shown in Fig. 3 and discussed below in detail. Recently, phytic acid has been reported to inhibit the enzymes such as cyclooxygenase-2 (COX-2), human neutrophil elastase, lipoxygenase, microsomal prostaglandin E synthase-2, and tyrosinase using in silico approach [55].
Phytic acid as 5-alpha-reductase inhibitor 5-alpha-reductase is an enzyme which catalyzes conversion of testosterone to dihydrotestosterone. In men elevated enzyme activity is associated with benign prostatic hypertrophy and premature baldness.

Antioxidant activity of phytic acid
Phytic acid has been reported to inhibit the hydroxyl radical formation [32,33] and lipid peroxidation activities [1,34]. In other study, phytic acid extracted from Kenyan local vegetables and grains have been shown to possess 2,2-diphenylpicrylhydrazyl radical scavenging activity [16]. Furthermore, phytic acid has been reported to exhibit antioxidant activity [35].

Antiplatelet and anti-angiogenic activity of phytic acid
Vucenik et al. [36] reported that phytic acid inhibits human platelet aggregation in a dose-dependent manner under in vitro condition. 5 years later, phytic acid has been reported to possess anti-angiogenic activity against both in vitro and in vivo induced angiogenesis [37].

Antiulcer activity of phytic acid
Ulcer is a common GI disorder. Ulcers are lesions on the srfuace of skin or a mucous membrane clinically characterized by a superficial loss of tissue. Phytic acid has been reported to possess antiulcer activity against ibuprofen, ethanol, and cold stress-induced ulcers in experimental rats [19].

Narayanaswamy and Esa
Phytic acid has been reported to inhibit the 5-alpha-reductase (type 2) activity using in silico study, which could prevent prostate cancer and hair fall [56].

Phytic acid derivative (PP-56) as aldose reductase inhibitor
Aldose reductase is the key regulatory enzyme in the polyol pathway, which catalyzes glucose to sorbitol. Elevated enzyme has been implicated in the development of diabetic retinopathy, leading cause of blindness. Phytic acid derivative, namely D-myo-inositol 1,2,6-trisphosphate (PP-56) has been reported to modulate the aldose reductase activity against streptozotocin-induced diabetic rats, which could prevent diabetic cataract formation [57].

Phytic acid as COX-2 inhibitor
COX is the key regulatory enzyme which catalyzes the conversion of arachidonic acid to prostaglandins, where cyclooxygenase-2 is mainly an inflammatory, inducible enzyme. Phytic acid has been reported to suppress the COX-2 expression in azoxymethane-induced colon cancer cells [58].

Myo-inositol phosphate ester (hydrolyzed product of phytic acid) as lipase inhibitor
Lipase is an enzyme which catalyzes the hydrolysis of fats. Elevated enzyme activity is associated with inflammatory or neoplastic disease of the pancreas. Myo-inositol phosphate ester has been reported to inhibit the lipase activity [59].

Phytic acid as matrix metalloproteinase-2 & 9 (MMP-2 & 9) inhibitor
MMP's are a group of zinc-dependent endopeptidase which capable of degrading extracellular matrix and are involved in remodelling and turnover of dermis [18]. Phytic acid has been reported to modulate the MMP-2 gene expression in colon cancer cells [60]. In other study, phytic acid has been reported to modulate both the MMP-2 and 9 gene expressions against phorbol-12-myristate 13-acetate stimulated colon cancer cells [61].

Phytic acid as pepsin inhibitor
Pepsin is a digestive enzyme which capable of degrading food proteins into peptides. Pepsin is one of the main causes of mucosal damage during laryngopharyngeal reflux. Phytic acid has been reported to inhibit the pepsin activity [62].

Phytic acid as polyphenol oxidase (PPO) inhibitor
PPO is copper-containing enzyme having both catecholase and cresolase activity. It plays defence role against pathogens and responsible for browning reactions. Phytic acid has been reported to inhibit the PPO activity, which could prevent browning of apple [63].

Phytic acid as protease inhibitor
Protease is a digestive enzyme, which hydrolysis protein into shorter fragments. It occurs in all organisms from prokaryotes to eukaryotes to viruses. Phytic acid has been reported to inhibit the protease activity in fish [64].

Phytic acid as β-Secretase (BACE-1) inhibitor
BACE-1 is a rate-limiting enzyme involved in production and deposition of amyloid-β-peptide (Aβ). It is now emerging as marker enzyme for the treatment of Alzheimer's disease. Phytic acid has been reported to inhibit the BACE-1 activity, which could prevent Aβ accumulation [65].

Phytic acid as tyrosinase inhibitor
Tyrosinase is the main regulatory enzyme in melanogenesis process particularly in the first two steps such as (i) tyrosine hydroxylation to 3, 4-dihydroxyphenylalanine (DOPA) and (ii) the oxidation of DOPA to dopaquinone. Graf et al. [4] have reported phytic acid, as inhibitor of mushroom tyrosinase. In other study, phytic acid containing formulation (Amelan M) has been shown to reduce pigmentation in melasma patients [66].

Phytic acid as xanthine oxidase (XO) inhibitor
XO is the key regulatory enzyme in purine metabolism. It catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Phytic acid has been reported to inhibit the XO activity which could prevent gout [67].

APPLICATIONS OF PHYTIC ACID
Phytic acid has been reported for five major applications (Fig. 4) such as adsorption and corrosion inhibition, cosmetic, dental care, industrial, and medical applications [68].
Among these applications, food industry applications of phytic acid have been reported as predominant one, where it has been added to alcoholic beverages, bread, canned seafoods, cheese, fish meal pastes, fruits, juices, meats, miso, noodles, soy sauce, and vegetables to prevent colour and as well as to prolong shelf life of products. In 1997, Food and Drug Administration of the USA regarded sodium phytate as generally recognized as safe status for using the same as preservative in baked foodstuffs [1]. Second medical applications of phytic acid have been gaining importance among researchers, due to its potential therapeutic value [68,69].

Narayanaswamy and Esa
of phytic acid. Encouraging pre-clinical studies suggest that phytic acid as a promising pharmaceutical agent for prevention and treatment of various diseases; however, more controlled clinical trials are required to demonstrate its novel therapeutic potential.

AUTHORS' CONTRIBUTIONS
RN (first author), who wrote the manuscript and submitted the same as part of PDF programme. NME (research supervisor), who had added value to it. All authors read and approved the final manuscript.

CONFLICTS OF INTEREST
The authors have declared no conflicts of interest.