FERULIC ACID: A NATURAL ESSENTIAL COMPOUND HAVING POTENTIAL INDUSTRIAL AND MEDICINAL PROPERTIES

FERULIC ACID: A NATURAL ESSENTIAL COMPOUND HAVING POTENTIAL INDUSTRIAL AND MEDICINAL PROPERTIES

Meghna Diarsa and Akshaya Gupte *

Natubhai V. Patel College of Pure and Applied Sciences, Vallabh Vidyanagar, Gujarat, India.

ABSTRACT: The ubiquitous compound 4-Hydroxy-3-methoxy cinnamic acid, also known as ferulic acid, constitute. A bioactive ingredient of many food that may offer a potential therapeutic effects useful in the treatment of cancer, diabetes, lung and cardiovascular disease. It is also effective against the disorders relative to oxidative stress, including certain neurodegenerative diseases. Ferulic acid is widely distributed in plants in either free or conjugated forms. Overall the pharmaceutical potential of ferulic acid can be attributed to its ability in scavenging free radicals. In recent years, it is also known to inhibit HNG-CoA reductase and activate glucokinase, thus contributing to the reduction of hypercholesterolemia and hyperglycemia. This review discusses the different properties of ferulic acid, establishing a relationship to several biological activities. FA is also used in a substantial amount in the food and cosmetic industries. So also, in recent years, it has been used as a cross-linking agent to manufacture edible food films. The review also discusses compound distribution, metabolism, and physiological role uses in the production of vanillin.

Keywords: Ferulic acid, Antioxidant, Shikimate pathway, Pharmacokinetics

INTRODUCTION: Ferulic acid (FA) is the most important hydroxycinnamic acid found abundantly in plant tissue ^1-3. In the plants, FA is rarely found in the free form. It is mainly found as an ester crosslinked with polysaccharides in the cell wall ^4-5. Ferulic acid was first isolated and purified from the plant Ferula foetida in 1866 and was chemically synthesized in 1925 ^6-8. FA is basically a phenylpropanoid and exists as a crystalline solid. FA also play a functional role in the structural integrity of the cell wall as it is associated with cellulose, hemicellulose, and lignin ^{9, 10}. Polyphenolic acids are secondary metabolites of a varying chemical structures and biological properties.

Naturally, FA is present in various plants and their residues such as corn bran, artichoke, peanut, wheat bran, coffee seeds, rice, oats, eggplant, beets, citrus, spinach, sugar beet, cane bagasse, neem, and pineapple ¹¹. FA exhibits low toxicity and possesses various bioactive properties such as antioxidant agent, antimicrobial, anti-inflammatory, antihyper-lipidic, anti-carcinogenic, anti-viral, anti-carcino-genic, anti-allergic, antithrombotic, and helpsin lowering cholesterol activity ^{1, 12-18}. One of the most important properties of FA is its antioxidant nature.

It is easily absorbed into the body and stays in the bloodstream for a longer period of time as compared to any other phenolic compounds. FA is also widely used in the food industry as a preservative because of its antioxidants and antimicrobial actions ¹⁹. It is also used in cosmetic industries, especially in skincare formulations, as a photoprotective agent. It can also be used as a supplement because it has free radical neutralization properties.

Source of Ferulic Acid: Ferulic acid is one of the important metabolites of lignin biosynthesis from phenylalanine and tyrosine and is ubiquitous in plant ²⁰. It occurs in plants in two forms: free and conjugated with hydroxyl acid or polysaccharides. Both forms together indicate the total FA. It is usually concentrated in the bran of grains, peel of fruits and roots, and peel of vegetables. The level of FA in various foods is summarized in Table 1.

TABLE 1: THE CONTENT OF FERULIC ACID IN DIFFERENT FOOD SOURCES

 In the fruits and vegetables ferulic acid found in conjugated form of hydroxyl acids, or with mono/disaccharides. In root vegetables, FA mainly occur as a dimer and /or esterified with arabinose. FA-Oryzanol is well-known example of sterol esterified ferulic acid, generally found in the grain. The extraction of FA provides environmental and economic encouragement for the production of pharmaceutical drugs, food, and nutraceutical industries. For the extraction of FA, various methods such as alkaline, acidic and enzymatic treatments are used. However, optimization of critical parameters such as time of extraction, pH and temperature are important for obtaining a high yield of ferulic acid. Alkaline treatment is a chemical method that involves hydrolytic cleavage of ester linkages between lignin and plant polysaccharides thereby leading to the release of the phenolic acids. The enzymatic treatment involves feruloyl esterase enzyme (E.C. 3.1.1.73) (FAE), a key enzyme for the extraction of the ferulic acid from the plant cell wall ^21-27. The enzyme acts through delignification and de-polymerization of polysaccharides and is able to hydrolyze the ester linkages between the arabinose sugar and ferulic acid ^28-33. Ferulic acid is insoluble in water at room temperature; however, it is soluble in hot water and solvents like ethyl acetate, ethanol, and ethyl ether, where 30% ethanol is also found to be the most suitable for FA extraction.

Structure and Chemical Properties of FA: Hlasiwetz and Barth in 1866 isolated proto-catechuic acid and resorcinol from a commercial resin of Ferula foetida ³⁴. Simultaneously they also obtained a yellow precipitate on the addition of divalent lead to an alcoholic resin solution. They washed the precipitated lead salt with alcohol, reconstituted the free acid, and determined its composition as C₁₀H₁₀O₄ (ferulic acid). In 1925 it was first synthesized chemically by amine catalyzed condensation of vanillin with malonic acid. The two isomers cis- and trans- isomers of FA were separated in 1957. The stereo clarity of ferulic acid was studied by ¹³CNMR in 1976 and was confirmed by X-ray crystallography analysis in 1988. The compound 3-(4-Hydroxy-3-methoxyphenyl)-2 propenoic acid is commonly known as ferulic acid. It is also known as 3-methoxy-4-hydroxycinnamic acid, caffeic acid 3-methyl ether, and confidence acid. Fig. 1 represents the structure of Ferulic acid and Isoferulic acid ³⁵.

FIG. 1: CHEMICAL STRUCTURE OF FERULIC ACID AND ISOFERULIC ACID

Ferulic acid extracted and isolated from plant exist as the trans- isomer. During the storage of cis and trans ferulic acid in water at room temperature, slow isomerization results in an equilibrium ratio of 23% cis and 77% trans.

Other Properties of Ferulic Acid: Ferulic acid is a strong dibasic acid. The dissociation of the first proton generates a carboxylate anion whereas the second proton generates a phenolate anion. A high degree of the phenolate anion increases its acidity relative to other phenolic acids. Cis-phenolic acid does not crystallize but forms a yellow oil with a UV maximum at 316 nm in ethanol ³⁶. Trans-ferulic acid is a colorless substance that possesses orthorhombic needle-like structure and is crystallized in hot water. FA has a molecular weight of 194.18 with a melting point of 170°C ^{37, 38}. It is soluble in ethanol, ethyl acetate, and hot water and sparingly soluble in benzene and petroleum ether too. Trans-ferulic acid absorbs UV strongly with an absorption maxima at 284 nm and at 307 nm in solution at pH 6.0 exhibits a strong fluorescence. Numerous chromatographic methods are available to determine the quality as well as quantity of ferulic acid.  The detection methods include High-pressure liquid chromatography (HPLC), Gas chromatography (GC), Capillary electrophoresis, electrochemical (EC), Thin-layer chromatography (TLC), High-performance thin layer chromato-graphy (HPTLC), and UV spectrometry method, HPLC-MS, Ultra performance liquid chromato-graphy (UPLC) coupled with electrospray ionization ³⁹.

Metabolism and Physiological Function: The principal pathway for the biosynthesis of ferulic acid in the plant is shown in Fig. 2. Ferulic acid is formed through the shikimate pathway starting from the two amino acids i.e., L-phenyl amine and L- tyrosine ⁴⁰. The two reactions are initiated by the enzyme phenyl amine-lyase and tyrosine ammonia-lyase ⁴¹. These enzymes convert the amino acids to trans-cinnamates and ρ-coumarate, respectively. Furthermore, ρ-coumaric acid gets converted into FA by hydroxylation followed by methylation with methionine acting as a donor of a methyl group which is catalyzed by S-adenosyl l-methionine. The subsequence of oxidation and methylation reactions give rise to other aromatic compounds like di- and tri-hydroxycinnamate derivatives, which can be further employed in the formation of lignin. Oxidative degradation of ferulic acid leads to vanillin and guaiacol. Flavonoids can also be synthesized as a byproduct.

FIG. 2: SYNTHESIS OF FERULIC ACID VIA SHIKIMATE PATHWAY ⁶

In-vivo studies in rats have shown that FA can be metabolized to a number of other metabolites such as FA glucuronide, FA-sulfate, FA-sulfoglucuronide, di-hydroferulic acid etc. Many researchers reported that major pathway of FA metabolism is in the conjugation with glucuronic acid/ sulfates. The conjugation of FA takes place in the liver by the action of sulfotransferase and UDP glucuronosyl-transferase ⁴².

FA has various physiological roles such as it crosslinking with vicinal pentosane chain arabin-oxylase, and hemicelluloses in cell walls which increases extensibility during cell elongation. It also acts as a germination inhibitor. FA has capability topromote the reduction in the release of ferritin iron. FA exhibits allelopathic function in the plant by regulation of plant growth via root interaction.

Uses and Potential Application of Ferulic Acid:

Ferulic Acid as an Antioxidant: The human body is affected by the formation of free radicals through endogenous and exogenous factors, which may cause many diseases. These exogenous factors include Ultraviolet light, air pollutions, and cigarette smoke, which may generate free radicals like Superoxide, H₂O₂, O^-₂, ^.OH, and NO⁴³. 1990. Superoxide and hydroxyl radicals can also be formed by the endogenous process in the presence of oxygen, adrenaline, flavone nucleotide, thiol compound, and sugars. These oxidative free radicals may affect healthy human cells adversely; thus, it becomes necessary to remove such toxic-free radicals ⁴⁴. The human body possesses several enzymes in order to neutralize the above mention free radicals. Enzymes known as superoxide dismutase (SOD), catalase and glutathione peroxidase have an antioxidant activity against free radicals. When there is an elevated level of oxidative stress, some additional antioxidants are also required to nullify oxidative stress. Ferulic acid is a ubiquitous plant constituent, and its antioxidant potential can be attributed to its structural characters. FA contains phenolic nucleus and unsaturated side chain; it is resonance stabilized phenoxy radical which accounts for its potential antioxidant activity ⁴⁵. Ferulic acid enhance the expression of the antioxidant enzymes, including superoxide dismutase (SOD) and catalase. Antioxidant mechanism of ferulic acid is a very complex mechanism. Fig. 3 represents the resonance stability of ferulic acid. It is based on the inhibition of the formation of reactive oxygen spp. on nitrogen as well as it also neutralizes the radicals ⁴⁶. The dibasic activity of FA is mainly due to the presence of carboxyl and phenolic hydroxyl groups. FA has a free radical scavenging activity and it also act as an inhibitor of enzyme which is responsible for generation of free radicals ⁴⁷. As a secondary antioxidant, ferulic acid is able to bind transition metals such as iron and copper, thus preventing the formation of toxic hydroxyl radical, which leads to cell membrane peroxidation. The structure of ferulic acid reveals a high degree of conjugated unsaturation and it is absorbed strongly in the UV range. Absorption of UV light initiates the formation of phenoxy radicals leading to its cis- trans- isomerization. Strong absorption of U.V light may also contribute to strong antioxidant activity. 3-methoxy 4-hydroxycinnamic acid injected into the human body, utilized and excreted in the urine in as derivatives of phenyl propionic and glycin conjugates i.e. 3-methoxy 4-hydroxyphenyl.

FIG. 3: RESONANCE STABILITY OF FERULIC ACID RADICALS

Anti-diabetic Effect: Diabetes mellitus is a metabolic disease caused due to hyperglycemia and excess production of free radicals, which leads to oxidative stress ⁴⁸. Diabetes is defined as an imbalance between the level of prooxidants and antioxidants in the biological system, thereby leading to cellular injury. The formation of free radicals is associated with the most common endocrine disorder. Ferulic acid possesses an antioxidant activity that helps to eliminate noxious streptozotocin agent, which is harmful to the insulin-producing beta cell in the pancreas. It has been reported that the administration of FA reduces blood glucose levels, free fatty acids, and TBARS (Thiobarbituric acid reactive substance) in diabetic rats ^{49, 50}.

Anti-cancer Effect: Cancer is an uncontrolled division of the cells, it is also known as a malignant tumor ⁴³. Anticancer properties of ferulic acid can be attributed to its antioxidant property to eliminate ROS and to stimulate the activity of antioxidant enzyme. It is known that a high concentration of ROS is produced in cancerous cells. FA has other prooxidant and antioxidant properties, which are considered as an important anticancer and apoptosis mechanism. Certain researchers have suggested that the consumption of grains, fruits and vegetables which have high content of FA help in reducing cancer ⁵¹. FA is a potent component of Chinese medicinal herbs such as Angelica sinensis, Cimicifaga heracleitolia, and Ligustiaum changxiong ⁵². Phytochemicals present in different plants and fruits may cause interference with intracellular signaling pathways. Effect of FA an oral cancer was studied by Mori et al., (1999) ⁵³, after chemically inducing carcinoma in rats where they revealed that the rats with FA administration showed chemo preservative activity against oral cancer. Fang et al., (2016) ⁵⁴ studied that an innovated hybrid anti-Alzheimer compound i.e. Ferulic acid-carbazole, reveal moderate to strong inhibitory action against cholinesterase Azoxymethane induced colon cancer wherein they observed the enzymes glutathione-s-transferase and quinone reductase had high activities in mice treated with FA. Both the enzymes are responsible for the detoxification of liver and colon polyphenols, and FA compromises tumor suppression potential in breast cancer ^{6, 50, 55-56}. Gao et al., (2018) ²² studied the effect of ferulic acid in the Hela and Caski cells by increasing the concen-trations of ferulic acid. They found that a 2.0 mM concentration of phenolic acid inhibits the Hela cell (88%) and Caski cell (85.4%). It also inhibits the migration of the cells by reducing the MMP-9mRNA expression. It also induces protein expression like P53 and P21 and reduces the cyclic D1 and E levels.

Anti-Microbial and Antifungal Effect: Ferulic acid inhibits the growth and reproduction of viruses and bacteria. It shows the effect against various gram-positive, gram-negative organisms along with yeast ^57-58. FA shows a strong inhibitory effect against Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Citro bacterkoseri, Shigella sonnei, Acinetobacter baumanni ^{43, 50, 59}. The antimicrobial activity of FA is related to the inhibition of arylamine N-acetyltransferase, a specific enzyme that catalyzes the acetylation of arylamine in the bacteria. Treatment of ferulic acid also leads to irreversible changes in membrane properties such as hydrophobic changes, surface changes, and pore formation in the cell membranes with consequent leakage of essential intracellular constitutes ⁶⁰. FA extended its antifilarial effect through indirect apoptosis and by down regularly and by the attraction of level of some key antioxidants. Ferulic acid also contains antiparasitic properties. Ferulic acid extracted from Hibiscus mutabilis (Malvaceae) express microfiralicidal and macro-firalicidal activities in case of microfilaria (L₁) and adult of Setariacervi. FA expresses the antifilarial effect in Setariacervi through apoptosis, downregulating, and modifying the level of key anti-oxidants such as GSH, GST, and SOD. FA also inhibits the growth of the yeast Dekkerabru xellensis ⁶¹.

Anti-inflammatory Effect: Acute inflammation is multiple processes which are mediated by activated immune cells. Macrophages play an important role in different immunological phenomenon such as production of pro-inflammatory cytokines and inflammatory mediators (ROS, nitric oxide Posta glands) ⁶². The efficiency of some inflammatory mediators like prostaglandin E2, tumor necrosis factor-alpha, and iNOS (inducible nitric oxide synthase) articulate decreases in the presence of 3-methoxy 4-hydroxycinnamic acid and other derivatives ^63-64. Ferulic acid is also used in the anti-inflammatory drug.

Use of FA in Foods and Cosmetics: FA has tremendous applications in the food and cosmetics industries. Ferulic acid has the ability to inhibit the peroxidation of fatty acids. In Japan, ferulic acid used in the preservation of oranges and stabilizes the lard and soybean oil ⁴¹. It also promotes the viscosity and emulsifying properties of food. Another application is, it is widely used in the development of edible films for food and drug packaging. Ferulic acid stabilizes the solution of vitamin C and E, which is used in the skin ointment and sunscreen lotion to doubling the photoprotection of skin (keratinocytes, collagen and fibroblasts) ⁴⁶. The researchers revealed that 3-methoxy 4-hydroxycinnamic aid is a competitive inhibitor with tyrosine, which suppresses the formation of melanin ^65-66. The phenolic nucleus and conjugated side chain are present in the structure of ferulic acid, which absorbs the U.V. light and stabilize the phenoxy radicals. It also expresses the defense mechanism against the U.V. rays, bright beams, and photodamage ⁶⁷.

Bioconversion of Ferulic Acid into Vanillin: Ferulic acid is a precursor of commercially valuable molecules. Vanillin (4-hydroxy 3-methoxybenzaldehyde) is an aromatic flavoring compound is used in the food industries, pharmaceuticals, and other industries. Vanillin forms as an intermediate during the microbial degradation of ferulic acid ⁶. Vanillin (75%) is used in the food industries like chocolate and ice cream to give flavor. It is also used for making the good quality of the fragrances ². Pharmaceutical industries use vanillin to avoid the unpleasant odor and taste of the medicines ⁶. Vanillin is widely used for the production of several drugs such as aldomet, dopamine, papaverine, and L-Dopa and as an antifungal agent ⁶⁸.

Vanillin was unknown until the vanilla beans found by Cortez in the Aztec kingdom of Montezuma in 1520 ². In 1858, Vanillin was isolated from the vanilla pod by the Theodore Nicolas Gobley ^{50, 68}. Vanilla is a mixture of two different species of vanilla orchids: Vanilla planifolia and Vanilla tahitensis. Fig. 4 shows the conversion of ferulic acid into vanillin. The conversion of vanillin from ferulic acid is a two-step process. Feruloyl CoA synthetase and enoyl CoA hydratase/aldolase convert the ferulic acid into vanillin. CoA thioester activates the ferulic acid, which is catalyzed by the fcs gene. Ferulyl CoA is hydrated by ech gene and cleaved to vanillin and acetyl CoA⁴.

FIG. 4: CONVERSION OF VANILLIN FROM FERULIC ACID ⁴

CONCLUSION AND FUTURE PROSPECTS: The present review summarizes the evidence and information on the availability, synthesis, structure, and metabolism of ferulic acid. FA exhibits a wide range of therapeutic properties like antibiotic, antimicrobial, anti-inflammatory and antioxidant properties. The review also explains its use in food and cosmetic industries as well as an alternative for the production of vanillin. FA is still not fully exploited. Additional studies focusing on the application are essential for the development of new drugs. Food supplementation and cosmetic formulation are strongly encouraged as FA has a strong market of about 55 million dollars by 2025.

ACKNOWLEDGEMENT: Not applicable

CONFLICTS OF INTEREST:  Authors declares no conflict of interest

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    How to cite this article:

    Diarsa M and Gupte A: Ferulic acid: a natural essential compound having potential industrial and medicinal properties. Int J Pharm Sci & Res 2022; 13(2): 603-11. doi: 10.13040/IJPSR.0975-8232.13(2).603-11.

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