A Review on Isolation and Believed Mechanism of Action of Hydroxycitric Acid

Introduction

Hydroxycitric acid (HCA) is a derivative of citric acid that is found in different tropical plants such as Garcinia cambogia, Garcinia atroviridis, Garcinia indica, and Hibiscus subdariffa.1It is also known as hydroxycitrate¹ .

HCA, an α-, β-dihydroxy tricarboxylic acid, is a component present mainly in the rind of the fruit Garcinia cambogia also called as Garcinia gummi gutta and is responsible for its anti-obesity property¹ . This natural product contains around 10 to 30% HCA, which can be separated in the free structure, as a mineral salt oras a lactone. HCA is available as its different salts, for example, calcium, magnesium, and potassium just as their blends. HCA is normally advertised as a weight reduction enhancement either alone or in blend with different enhancements. A few creators have proposed that HCA causes weight reduction by intensely hindering the catalyst adenosine triphosphate-citrate-lyase. HCA has additionally been accounted for expanding the release or accessibility of serotonin in the brain, in this manner prompting appetite suppression. Other hypothesized weight reduction mechanisms incorporate hindrance of pancreatic alpha amylase and intestinal alpha glucosidase, subsequently prompting a decrease in carbohydrate metabolism.² It exists in four different isomers namely (+) - and (-)-hydroxycitric acid, and (+) - and (-)-allo-hydroxycitric acid. The (-)-hydroxycitric acid isomer is the one found in Garcinia also known as 2S,3S–HC³ .

HCA hinders adenosine triphosphate citrate lyase and has been utilized in the treatment of weight reduction. Adenosine triphosphate citrate lyase, the enzyme responsible for catalysing the extra mitochondrial cleavage of citrate to oxaloacetate and acetyl-coenzyme A (acetyl-CoA), a building block of fatty acid synthesis. It also hinders lipogenesis in a few tissues, for example, liver, fat tissue, and small digestive system, where carbohydrates are changed over to unsaturated fats. As of now double or triple salts of calcium, magnesium and potassium rather than the single salt of HCA are being utilized because of their higher solubility and stability⁴ .

Sources of HCA

Garcinia atroviridis, known as asamgelugur, asamgelugo, or as am keping, is a huge perpetual plant normally found in evergreen forests in the southern locale of Thailand and Malaysia. It is generally cultivated, particularly in the northern states. The tree develops to a height of more than 20 m and has a long trunk, smooth dim bark, and hanging branches. The leaves are dim green, gleaming, long and tight with a pointed tip, and improved edges. The flowers are dim red. The round natural products are borne independently on twig finishes around 7–10 cm in width. The ready natural products are splendid orange yellow in shading. The natural product contains citrus acid, tartaric acid, malic acid, ascorbic acid, hydroxycitric acid, and flavonoids.⁵

Uses

It is used to treat ear-ache, cough, throat disturbance, dandruff, improving blood circulation, and as a laxative. Sun-dried cuts of the organic products, locally known as "asamkeping", are monetarily accessible and are prominently utilized as a vegetable serving of mixed greens and is viewed as amazingly acrid.⁶

Garcinia indica, a plant in the mangosteen family (Clusiaceae), regularly known as kokum, is an organic product bearing tree that has culinary, pharmaceutical, and mechanical employments. Garcinia indica is an evergreen, monoecious tree. The tree can grow as high as 18 m. On development, the trees accomplish a pyramid shape. The natural product is an orange size purple shading berry. The product of the plant contains five to eight huge seeds which record for 20-23% of the organic product's weight. The portions represent 61 percent of the heaviness of the seed, while the oil substance of the piece represents about 44%. The seeds are compacted and inserted in an acidic pulp.⁷

Uses

The seed of Garcinia indica contains 23–26% Kokum butter. The sleek concentrate called Kokum butter is utilized in ointments and suppositories. It has applications in skin and hair items, acne products, and skin tonics. The skin of the natural product is a decent wellspring of hydroxycitric acid, which has been professed to adjust lipid digestion⁸ .

Garcinia gummi-gutta is a tropical type of Garcinia and family, Clusiaceae local to South-eastern Asia, beachside Karnataka/Kerala, India, and west and central Africa with previous scientific name, Garcinia cambogia. It grows in most damp woods. Otherwise called brindleberry, Malabar tamarind and kudampuli (pot tamarind). With narrow skin and profound vertical projections, the product of G. gummi-gutta and related species extend from about the size of an orange to that of a grapefruit; G. gummi-gutta looks progressively like a little pumpkin and is yellowish, greenish, or now and then rosy pumpkin in shading. The leaves of the tree are dim green, glossy, oval shaped, extending from 2½ to 3½ inch long and from 1 inch to 1½ inch in width⁹ .

Uses

The rind of the fruit is commonly used as a food preservative, flavouring agent or food-bulking agent, and as a traditional remedy to treat constipation, piles, rheumatism, oedema, irregular menstruation, and intestinal parasites in many Asian countries. The tree flowers during the hot season and fruits ripen during the rainy season. Fruit rind is also eaten raw, perhaps at meals as an appetizer in parts of India. The dried fruit rind of G. cambogia combined with salt and other organic acids can lower the pH and thus provide a bacteriostatic effect for curing fish; this method of preservation of fish is known as Colombo. The fruit rind is also used in rickets, enlargement of spleen, and for healing of bone fractures. A decoction of fruit rind is given as a purgative in the treatment of intestinal parasites, bilious digestive conditions, dysentery, rheumatism, and in the treatment of tumors. The extracts are also used as a cardio-tonic to treat angina. In veterinary practice, the extract is also used as a rinse for diseases of the mouth¹⁰.

Hibiscus sabdariffa L. (Hs), also known as roselle, is ayearly, straight, thick, herbaceous plant that can raise up to 8 ft. (2.4 m) tall, tubular, and typically red stems. The leaves are different, 3 to 5 in (7.5–12.5 cm) long. The leaves of young saplings and upper leaves of older plants are simple; lower leaves are deeply 3 to 5 or even 7 lobed. Flowers, borne singly in the leaf axils, are up to 12.5 cm wide, yellow or buff with a rose or maroon eye, and turn pink as they wither at the end of the day. At this time, the typically red calyx, consisting of 5 large sepals with a collar (epicalyx) of 8 to 12 slim, pointed bracts (or bracteoles) around the base, begins to enlarge, becomes fleshy, crisp but juicy.¹¹

Uses

It is one of the most important species grown commercially as a fibre plant.The leaves are used for animal fodder and fibre.In Malaysia, the oil is used to produce scrubs and soaps¹¹.

Synthesis of Hydroxycitric Acid

Hydroxycitric acid can be synthesised using citric acid as starting material. Citric acid first undergoes dehydration to form aconitic acid, which forms hydroxycitric acid via oxidation. The optimum conditions of aconitic acid is that 1 M citric acid reacts with 56% sulphuric 270mL to obtain aconitic acid after 7 h reflux in 140^o C. Its melting point is 186^o C. The optimum condition for Hydroxycitric acid is that 2 M oxidant reacts with 1 M aconitic acid in 50 for 7h, and obtained hydroxycitric acid whose yield is about 80%¹².

Isolation of HCA

It was demonstrated that isolationof (-)-HCA can be done on a large scale from the dried rinds of G. cambogia. The method consisted of extracting the acid by cooking the raw material with water under pressure (10 lb/in. 2 for 15 min). The extract was concentrated and pectin was removed by alcohol precipitation. The clear filtrate was neutralized with alkali, passed through cation exchange resin for recovery of the acid, which was then concentrated and dried. The crude dried mass was extracted with ether and recrystallized to give small needle shaped crystals of lactone. Another method for the isolation of (-)- HCA from G. cambogia was by using acetone. The acetone extract was concentrated and the acid was taken up in water. The aqueous solution yielded the lactone on evaporation. A process was developed for the aqueous extraction of (-)-HCA from Garcinia rinds. It was reported the preparation of(-)-HCA concentrate from Garcinia rinds with 23-54% (-)-HCA and 6-20% lactone¹³.

HCA and Its Salts

Commercially, HCA is available as Na⁺ salt, Ca²⁺ salt, K⁺ salt, Mg²⁺ salt, Ca²⁺/K⁺ double salt and Mg²⁺/K⁺ double salt. The solubility of these compounds, which can affect bioavailability, ranges from less than 50 to 100%¹⁴. HCA-SX or Super Citric Max (calcium-potassium double salt) was demonstrated to be completely soluble in water and confers higher BA than HCA-Ca (calcium salt ) when evaluated in Albino Wister rats.

Roles of Calcium and Potassium in Weight Management

Potassium (K⁺ ) and calcium (Ca²⁺) are important ions in a number of metabolic pathways influencing energy expenditure, leptin metabolism and weight control. K⁺ is a major mineral in the body. Severe K⁺ deficiency causes cardiac arrhythmias, muscle weakness, and glucose intolerance, while moderate deficiency leads to increased blood pressure and salt sensitivity, an increased risk of kidney stones and increased bone turnover. Inadequate K⁺ intake may also increase the risk of cardiovascular disease, particularly stroke, and may disturb intracellular pH homeostasis. K⁺ and Ca²⁺ flux may play important roles in coupling intracellular energy production to leptin secretion. However, meta-analyses indicate that increased Ca²⁺ and K⁺ intake should be the focus on dietary recommendations, rather than restriction of Na+ in the management of such disorders as hypertension. Evidence demonstrates that diets rich in Ca⁺ and K⁺ produce a potent antihypertensive effect¹⁵. Dietary Ca²⁺ also plays a crucial role in regulating energy metabolism. High Ca²⁺ diets have been shown to inhibit fat synthesis and storage in adipocytes and reduce weight gain during over-consumption of an energy-rich diet. High Ca²⁺ intake was shown to increase lipolysis and preserve thermogenesis during caloric restriction, accelerating weight loss. In contrast, low Ca²⁺ diets have been shown to inhibit body fat loss¹⁶.

Increasing Energy Expenditure

It has been demonstrated that HCA-SX either alone or in blend with chromium and Gymnemasylvestre extract (GSE) has been shown to successfully advance breakdown of body fats. Note worthy increment in levels of serum free unsaturated fat and glycogen content in gastrocnemius muscle of mice after intense organization of 10mg HCA/mice was witnessed. Be that as it may, prolong administration of 10mg HCA/mouse every day for 3 weeks increased continuance practice execution in mice during running by advancing lipid oxidation and lessening glycogen utilization. Short-term administration of HCA has additionally been seen to upgrade fat oxidation altogether bringing down sugar oxidation during exercise in competitors and untrained ladies¹⁷. Improvement of lipid digestion by HCA in human guineas pigs can likewise be derived from many-overlap expanded urinary concentration of metabolites like malondialdehyde (MDA), acetaldehyde, formaldehyde, and acetone. With expanded urinary discharge, these metabolites are believed to be a result of upgraded ß-oxidation of fat in body tissues. Comparable upgraded urinary discharge of fat metabolites has likewise been seen in stout human subjects just as Sprague-Dawley rats getting HCA-SX alone or in mix with niacin bound chromium (NBC) and gymnemasylvestre extract (GSE), in this way proposing HCA-SX advances breakdown of fats¹⁸.

Effect of HCA on Appetite Suppression

In prior in vitro examinations, it has been shown that HCA-SX-induce high serotonin discharge and serotonin receptor reuptake inhibitor (SRRI) in separated rat brain cortex and proposed that serotonin guideline might be a significant instrument of hunger suppression by HCA-SX. HCA may advance weight decrease by two mechanisms.¹⁹

One probable mechanism include the hindrance of ATP citrate lyase, a key protein liable for advancing fat synthesis that would restrain the accessibility of acetyl coenzyme (acetyl CoA) for lipid synthesis during carbohydrate intake. Accordingly, carbon is diverted to glycogen synthesis.²⁰

A second possible mechanism for an anorectic impact of HCA holds that by decreasing acetyl CoA, malonyl CoA levels are discouraged thereby diminishing negative feedback on carnitineacyl transferase. This prompts to increase lipid transport into the mitochondria and wasteful oxidation with resultant ketone body development. Ketones are purported appetite suppressants.²¹

But, it was exhibited that HCAL shows better activity regarding appetite suppressant and decrease in weight gain and this might be because of continuous transformation of HCAL into HCA as it gets used by the body. HCAL may therefore go about as a prodrug. Once HCAL gets changed over into HCA it pursues a similar mechanism of activity as HCA in lessening body weight and appetite suppression²².

Conclusion

In this review, detailed information about HCA, the active ingredient in Garcinia cambogia and related plants are provided. The mechanisms of actions known in the literature are listed which suggests that the plant imparts its actions through multiple targets and may act with combined mechanisms. The importance and efficiency of its different salt forms in terms of its bioavailability and effectiveness in reducing obesity are also highlighted.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

The authors are thankful to the management and staff of Department of Pharmaceutics, Karnataka College of Pharmacy, Bangalore for their encouragement.