Pentacyclic triterpenoids

Pentacyclic Triterpenoids

1. Identity, Chemistry, and Classification

Pentacyclic triterpenoids are considered as compounds with a 30-carbon-atom basic structure that are widely spread across the plant kingdom, and to a limited extent in marine organisms. Terpenoids are a class of compounds and their derivatives with a molecular scaffold based on isoprene units, widely distributed in nature, and are major components of secondary metabolites such as plant essential oils, resins, and pigments. They are classified into monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, tetraterpenes, and polyterpenes based on the number of isoprene units in their molecular structure. Triterpenes, composed of a basic skeleton of 30 carbon atoms, are important plant secondary metabolites found in nature either in free form or as glycosides or esters bound to sugars.

Pentacyclic triterpene acids are a class of secondary terpenoids resulting from the oxidative cyclization of squalene, with oleanane, ursane, and lupane being their biogenetically earliest and most widespread skeletal types. Typical pentacyclic triterpenoids such as lupane, oleanane, ursane-type, and friedelane-type are derived from the baccharenyl cation, and these cyclized skeletons can be further decorated by cytochrome P450 monooxygenases, cytochrome P450 reductases, and UDP-dependent glycosyltransferases, thereby generating numerous pentacyclic triterpenoids.

The first committed step of triterpenoid biosynthesis is the cyclization of 2,3-oxidosqualene, a pivotal step catalyzed by oxidosqualene cyclase (OSC) enzymes in plants. In this enzymatic mechanism, the 2,3-oxidosqualene substrate adopts a chair–chair–chair conformation, leading to the formation of the dammarenyl carbocation intermediate before cyclization, giving rise to various triterpenoid types such as ursane, oleanane, lupane, and other diverse skeletal structures.

1.1 Principal Skeletal Classes

Pentacyclic triterpenoids usually have lupane, hopane, ursane, oleanane, taraxaterane, and friedelane skeletons. The most pharmacologically studied classes are described below:

• Oleanane-type: Oleanolic acid (OA, 3β-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid with widespread occurrence throughout the plant kingdom. This compound and its derivatives possess several interesting pharmacological activities, such as anti-inflammatory, antioxidant, anticancer, and hepatoprotective effects.
• Ursane-type: Ursolic acid (sometimes referred to as urson, prunol, malol, or 3β-hydroxyurs-12-en-28-oic acid) is a pentacyclic triterpenoid identified in the epicuticular waxes of apples as early as 1920 and widely found in the peels of fruits, as well as in herbs and spices like rosemary and thyme. Ursolic acid possesses important biological effects, including anti-inflammatory, anticancer, antidiabetic, antioxidant, and antibacterial effects, but its bioavailability and solubility limits its clinical application.
• Lupane-type: Betulinic acid (BA) and betulin (B) are pentacyclic triterpenoids within the lupane series, being mainly investigated as potential anticancer molecules.
• Oleanane glycoside (Saponin): Glycyrrhizin (glycyrrhizic acid; glycyrrhizinate) constitutes 10–25% of licorice root extract and is considered the primary active ingredient. Glycyrrhizin is a saponin compound comprised of a triterpenoid aglycone, glycyrrhetic acid (glycyrrhetinic acid; enoxolone) conjugated to a disaccharide of glucuronic acid.
• Ursane triterpenoid glycosides (Centella asiatica): Asiatic acid is an aglycone of ursane-type pentacyclic triterpenoid and is the chief bioactive constituent from the extract of tropical medicinal plant Centella asiatica L. (family Umbelliferae). This plant is indigenous to Africa, Oceanic countries, and Southeast Asian countries including the Indian subcontinent. Asiaticoside and madecassoside are the principal glycosidic forms found in the same plant.
• Boswellic acids (Hopane-related): The β-pentacyclic triterpene acids in Boswellia serrata including 3-acetyl-11-keto-β-boswellic acid (AKBBA), 11-keto-β-boswellic acid (KBBA), β-boswellic acid (BBA), and 3-acetyl-β-boswellic acid (ABBA), represent the major bioactive boswellic acids in the gum resin.
• Friedelane-type: Triterpenoids found in Celastraceae species display mainly lupane, ursane, oleanane, and friedelane skeletons, exhibiting a wide range of biological activities such as antiviral, antimicrobial, analgesic, anti-inflammatory, and cytotoxic activity against various tumor cell lines.

1.2 Representative Compounds and Their Chemical Names

Oleanolic acid (OA), betulinic acid (BA), ursolic acid (UA), triptolide, and glycyrrhetinic acid (GA) are typical examples of pentacyclic triterpenoids. Despite their significant biological activities, poor water solubility and low bioavailability have limited further development and application.

• Ursolic acid: 3β-hydroxy-urs-12-en-28-oic acid; C₃₀H₄₈O₃
• Oleanolic acid: 3β-hydroxyolean-12-en-28-oic acid; C₃₀H₄₈O₃
• Betulinic acid: 3β-hydroxy-lup-20(29)-en-28-oic acid; C₃₀H₄₈O₃
• Glycyrrhizin / Glycyrrhizic acid: the principal saponin of Glycyrrhiza glabra, with a glycyrrhetinic acid (oleanane) aglycone
• Asiatic acid: an ursane-type aglycone from Centella asiatica
• Asiaticoside: the glycosidic form of asiatic acid
• AKBBA (3-acetyl-11-keto-β-boswellic acid): the primary pharmacologically active boswellic acid in Boswellia serrata

Betulinic acid and oleanolic acid are both constitutional isomers of ursolic acid. In free forms, triterpenoids are nonvolatile lipophilic substances that are soluble in organic solvents and insoluble in water.

1.3 Natural Sources

These compounds can be found in several medicinal plants and are natural constituents of the human diet, since they have been found in a great variety of fruits, vegetable oils, and cereals. In the Western world, the individual average human consumption of triterpenes is estimated to be approximately 250 mg per day, and in Mediterranean countries, the average intake could reach 400 mg per day.

Key botanical sources include:

• Ursolic acid is present in many plants, such as Mirabilis jalapa, as well as in many fruits and herbs used in daily life (e.g., apples, Plantago major, basil and holy basil, bilberries, cranberries, elder flower, peppermint, rosemary, lavender, oregano, thyme, hawthorn, and prunes). Apple peels contain large quantities of ursolic acid and related compounds.
• Oleanolic acid and ursolic acid are triterpenoid compounds that exist widely in food, medicinal herbs, and other plants.
• Licorice (Glycyrrhiza glabra Linn) root and its extracts, such as glycyrrhizin, have a long history of use in traditional medicines, folk remedies, and as a sweetening and flavoring agent.
• Oleanane, ursane, and lupane, which are derived from β-amyrin, α-amyrin, and lupeol, respectively, represent the major pentacyclic triterpenoid scaffolds.
• Mimusops caffra, Ilex paraguariensis, and Glechoma hederacea have been reported as major sources of ursolic acid.
• Natural resources of pentacyclic triterpenoids are limited due to their low content in plant tissues and the long growth cycle of plants.

1.4 Common Forms and Preparations

Several pentacyclic triterpenes, including pentacyclic triterpene derivatives, are being marketed as therapeutic agents or dietary supplements around the world. Common commercial forms include:

• Standardized plant extracts: Powdered extracts of Boswellia serrata, Centella asiatica, and licorice root standardized to a defined percentage of the principal active triterpenoids
• Isolated aglycones: Purified ursolic acid, oleanolic acid, or betulinic acid in capsule or tablet form
• Glycosidic (saponin) preparations: Glycyrrhizin and asiaticoside preparations used in both dietary supplements and pharmaceutical products
• Topical formulations: Centella asiatica extracts are widely incorporated into cosmeceutical creams and gels for wound-healing and skin applications
• In recent years, researchers have developed a series of derivatives with enhanced biological activities and improved drug properties through structural modifications of these compounds, particularly achieving notable progress in the field of antitumor therapy.

2. Traditional and Historical Use

2.1 Asian Traditional Medicine Systems

In Asian countries, triterpenes are traditionally used as anti-inflammatory, analgesic, hepatoprotective, cardiotonic, and sedative agents.

Traditional Chinese Medicine (TCM): Traditional Chinese Medicine has long utilized licorice root, not only as a standalone remedy but also as a harmonizing agent in complex herbal formulas, believed to enhance the efficacy of other herbs while moderating their harshness. In Japan, glycyrrhizin has been used for more than 60 years as a treatment for chronic hepatitis C. Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, has been extensively used with considerable success.

Ayurveda: Boswellic acids, the triterpenes present in the gum resins of Boswellia serrata, have been traditionally used in the Ayurvedic system of medicine as an antioxidant and anti-inflammatory agent to manage diseases such as rheumatoid arthritis, chronic bronchitis, asthma, and chronic inflammatory bowel diseases and osteoarthritis. In Ayurveda, licorice root preparations containing glycyrrhizinic acid were recommended for digestive complaints, ulcers, and adrenal support.

Centella asiatica in Southeast Asian and Indian traditions: Although the leaf was initially given importance in the traditional pharmacopoeia of India, many modern investigators have advocated the use of the entire plant, including root, twigs, leaves, and seeds. The use of this herb can also be traced to China and other Southeast Asian countries, where it was used for fever, skin conditions, and treating inflammation-related diseases. In Assam, this herb has been traditionally used as an antimicrobial against gut infections and other gut ailments. During the middle of the twentieth century, Centella asiatica and its alcohol extracts were reported to have shown positive results in the treatment of leprosy in Western medicine.

The traditional use of Centella asiatica or asiaticoside includes promoting wound healing, treatment of skin diseases, skin disorders, and chronic inflammatory diseases.

2.2 Licorice in Ancient Mediterranean and Middle Eastern Traditions

Licorice is a small perennial herb that has been traditionally used to treat many diseases, such as respiratory disorders, hyperdipsia, epilepsy, fever, sexual debility, paralysis, stomach ulcers, rheumatism, skin diseases, hemorrhagic diseases, and jaundice. Ancient civilizations such as the Egyptians, Greeks, Chinese, and Indians revered licorice for its remarkable healing properties. Historical remedies often relied on glycyrrhizinic acid to soothe respiratory ailments such as coughs, bronchitis, and sore throats, as it acts as a natural demulcent and expectorant.

2.3 Triterpenoid-Rich Herbs in Indian Ethnomedicine

Achyranthes aspera L. is a well-known herb commonly used in the traditional system of Indian medicine to treat various disorders, such as cough, dysentery, gonorrhea, piles, kidney stone, pneumonia, renal dropsy, skin eruptions, and snake bite. This plant contains detectable quantities of betulinic acid, oleanolic acid, and ursolic acid. From ancient times, plants have remained the most trusted source of medicine for the treatment of diverse disease conditions.

3. Key Constituents, Active Compounds, and Mechanisms of Action

3.1 Anti-Inflammatory Mechanisms

Pentacyclic triterpenoids have garnered widespread attention due to their diverse biological activities, including anti-inflammatory, antiviral, and antitumor effects.

These compounds exert their effects by modulating important signaling pathways such as NF-κB, PI3K/Akt, and MAPK.

Regarding boswellic acids specifically: AKBBA was found to be a potent inhibitor of leukotriene-mediated inflammatory pathways and 5-lipoxygenase (5-LO) activities. It has been shown to inhibit inflammatory mediators, matrix metalloproteinases, and other adhesion factors in in vitro studies.

Regarding glycyrrhizin and its metabolites: Glycyrrhizin, its metabolite glycyrrhetic (glycyrrhetinic) acid, and other licorice-derived compounds exert potent anti-inflammatory effects via a wide range of mechanisms including high mobility group box 1 protein (HMGB1) inhibition, gap junction blockade, and α_2A-adrenoceptor antagonism.

The anti-inflammatory activity of betulinic acid is, at least in part, due to its capacity to inhibit enzymes involved in leukotriene biosynthesis, including 5-lipoxygenase.

3.2 Hepatoprotective Mechanisms

Both oleanolic acid and ursolic acid are effective in protecting against chemically induced liver injury in laboratory animals. Oleanolic acid has been marketed in China as an oral drug for human liver disorders. The mechanism of hepatoprotection by these two compounds may involve the inhibition of toxicant activation and the enhancement of the body's defense systems.

Oleanolic acid reduced the release of serum liver enzymes and inflammatory factors and prevented concanavalin A-mediated damage to the liver. It elevated the expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and decreased the phosphorylation of c-Jun NH2-terminal kinase (JNK).

It has been suggested that the mechanism underlying oleanolic acid's hepatoprotective effect is OA-induced inhibition of the expression of CYP2E1.

3.3 Anticancer Mechanisms

Mechanisms such as cytotoxicity, DNA polymerase inhibition, regulation of apoptosis, change in signal transductions, interference with angiogenesis and dedifferentiation, antiproliferative activity, and metastasis inhibition are thought to be responsible for the anticancer effect of pentacyclic triterpenoids.

Pentacyclic triterpenoids such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models.

In most cases, cytotoxicity values of the natural triterpenes are related to their ability to cause cancer cell apoptosis and inhibit different biochemical pathways.

3.4 Antiviral Mechanisms

The pentacyclic triterpenoids (PTs) are a diverse class of natural products from plants composed of three terpene units. They exhibit antitumor, anti-inflammatory, and antiviral activities. Oleanolic, betulinic, and ursolic acids are representative PTs widely present in nature with a broad antiviral spectrum.

Glycyrrhizin and glycyrrhizic acid have been shown to inhibit growth and cytopathology of numerous RNA and DNA viruses, including hepatitis A and C, herpes zoster, HIV, herpes simplex, and CMV.

Betulinic acid and dihydrobetulinic acid acyl derivatives have been found to have potent anti-HIV activity; 3-O-(3',3'-dimethylsuccinyl)-betulinic acid and dihydrobetulinic acid both demonstrated extremely potent anti-HIV activity in acutely infected H9 lymphocytes.

3.5 Antimicrobial Mechanisms

Pentacyclic triterpenoids, including α-amyrin, betulinic acid, and betulin, have been shown to exhibit analgesic, immunomodulatory, anti-inflammatory, anticancer, antioxidant, antifungal, and antibacterial activities. In studies of the antimicrobial activities and targets of these compounds in sensitive and multidrug-resistant S. aureus, these compounds acted synergistically and have different targets from conventional antibiotics.

3.6 Cytochrome P450 Interactions (Metabolic)

Oleanolic acid (OA) and ursolic acid (UA) are triterpene acids having a similar chemical structure and are found in plants worldwide. These materials are of interest as therapeutics because of their biological activities. Research using human liver microsomes has demonstrated that both OA and UA are capable of modulating the activities of cytochrome P450 enzymes, which has implications for potential drug interactions.

4. Scientific Evidence by Area of Use

4.1 Osteoarthritis and Joint Inflammation — Boswellic Acids

This is the area of pentacyclic triterpenoid use with the strongest clinical evidence base.

In a meta-analysis including seven clinical trials involving 545 patients, Boswellia and its extracts were reported to have a positive effect on relieving pain and stiffness, and improving joint function.

A double-blind, placebo-controlled human trial was conducted to evaluate the safety and efficacy of a standardized oral supplementation of Boswellin®, a novel extract of Boswellia serrata (BSE) containing 3-acetyl-11-keto-β-boswellic acid (AKBBA) with β-boswellic acid (BBA). A total of 48 patients with osteoarthritis of the knee were randomized and allocated to the BSE and placebo groups for intervention. Patients were administered BSE or placebo for a period of 120 days. The trial results revealed that BSE treatment significantly improved the physical function of the patients by reducing pain and stiffness compared with placebo.

Radiographic assessments showed improved knee joint gap and reduced osteophytes, confirming the efficacy of BSE treatment. BSE also significantly reduced the serum levels of high-sensitive C-reactive protein, a potential inflammatory marker associated with osteoarthritis of the knee. No serious adverse events were reported.

The dosage reported in that trial: A tablet form of BSE (169.33 mg containing 30% 3-acetyl-11-keto-β-boswellic acid [AKBBA]) was given orally twice daily for a period of 120 days in patients with osteoarthritis of the knee.

In a randomized, double-blind, placebo-controlled trial (N = 105), a standardized extract of Boswellia serrata gum resin (Boswellin® Super) administered for 90 days improved pain, stiffness, and mobility, while decreasing serum inflammatory marker levels in subjects with osteoarthritis.

Clinical studies have shown that Boswellia serrata extract not only has anti-inflammatory and anti-arthritis properties, but also improves pain and physical function. Evidence assessment: This represents the strongest human clinical evidence for any pentacyclic triterpenoid application, supported by multiple randomized controlled trials and a meta-analysis.

4.2 Hepatoprotection — Oleanolic Acid and Glycyrrhizin

Oleanolic acid has been marketed in China as an oral drug for human liver disorders. Oleanolic acid and ursolic acid have also been long-recognized to have anti-inflammatory and antihyperlipidemic properties in laboratory animals, and more research is warranted to develop therapy for patients.

In a preclinical study of hepatoprotection by the ursolic acid/oleanolic acid mixture: Liver injury was induced in male BALB/c mice by administering a combination of anti-tubercular (anti-TB) agents rifampicin, isoniazid, and pyrazinamide per os and daily for 11 weeks. The ursolic acid and oleanolic acid mixture at doses of 100 or 200 μg/mouse/day was subcutaneously injected throughout the entire study period. Animals treated with the mixture of triterpenic acids exhibited significantly decreased aspartate transaminase and alanine aminotransferase levels and amelioration of histopathological alterations produced by anti-TB drugs. The triterpene mixture was able to prevent the steatosis induced by the anti-TB drugs. This study was conducted in animals, not humans.

Regarding glycyrrhizin: In Japan, glycyrrhizin has been used for more than 60 years as a treatment for chronic hepatitis C. Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, has been extensively used with considerable success; in two clinical trials, SNMC has been shown to significantly lower aspartate aminotransferase levels and reduce lesions in the liver.

Evidence assessment: For oleanolic acid, hepatoprotective data are primarily from animal models and in vitro studies. Glycyrrhizin's hepatitis C application (intravenous SNMC) has clinical trial support, but primarily in Japan and for a narrow indication.

4.3 Anticancer Activity — Preclinical and Preliminary Evidence

The family of plant pentacyclic triterpenes and triterpenoids is intriguing in terms of their structures, spectrum of biological activity, and potential applications as new therapeutics. Many members of this family of plant secondary metabolites exhibit potent cytotoxicity in representative human cancer cell lines, antimicrobial activity, and other pharmacological effects.

Pentacyclic triterpenoids such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models.

Several studies have demonstrated that certain triterpenoids exhibit anticancer potential, with high selectivity for cancer cells and the ability to induce apoptosis-related death in most cases. Due to this specific action, several triterpenoids are currently being evaluated in phase I clinical trials.

Despite promising preclinical data, rigorous clinical trials are needed to verify their safety and efficacy.

Evidence assessment: The anticancer evidence for pentacyclic triterpenoids remains predominantly in vitro (cell lines) and animal model-based. Phase I human trials exist for some derivatives but peer-reviewed results of completed Phase II or III trials are not yet well established for isolated pentacyclic triterpenoids in oncology.

4.4 Antiviral Activity — Mixed Preclinical and Some Clinical Evidence

Liquorice constituents have been found to have anti-inflammatory, antioxidant, antiviral, anticancer, hepatoprotective, and neuroprotective properties.

Glycyrrhizin and glycyrrhizic acid have been shown to inhibit growth and cytopathology of numerous RNA and DNA viruses, including hepatitis A and C, herpes zoster, HIV, herpes simplex, and CMV.

Evidence assessment: Antiviral effects of glycyrrhizin against hepatitis viruses have some clinical support (particularly for intravenous administration in hepatitis C). For other viruses and for other pentacyclic triterpenoids, antiviral evidence is primarily in vitro and preclinical.

4.5 Wound Healing and Skin Effects — Centella asiatica Triterpenoids

A variety of medicinal herbs and bioactive compounds extracted from plant sources have exhibited therapeutic properties that are being currently investigated extensively for clinical use. The triterpenoids of Centella asiatica — principally asiaticoside, madecassoside, and asiatic acid — have been among the most studied for wound healing.

The available preclinical and clinical pharmacokinetic data suggest that asiatic acid is bioavailable in almost every tissue. It is distributed to many components of the body by binding with albumin.

Evidence assessment: Clinical evidence for topical Centella asiatica preparations in wound healing is modestly favorable, but the evidence from high-quality randomized controlled trials remains limited. Oral use for cognitive and systemic effects is primarily supported by preclinical data.

4.6 Antimicrobial Activity

Ursolic acid (UA), oleanolic acid (OA), and betulinic acid (BA), three hydroxyl pentacyclic triterpenoic acids naturally found in a large variety of vegetarian foods, medicinal herbs, and plants, have been investigated for antibacterial activity.

In studies of the antimicrobial activities and targets of α-amyrin, betulinic acid, and betulin in sensitive and multidrug-resistant S. aureus, these compounds acted synergistically and had different targets from conventional antibiotics. The inhibitory mechanisms against S. aureus in novel targets and pathways should stimulate further research to develop these compounds as therapeutic agents for infections caused by S. aureus.

Evidence assessment: Antimicrobial effects have been demonstrated primarily in in vitro minimum inhibitory concentration studies and in animal models. No large-scale human clinical trials have established clinical efficacy for infectious disease indications.

4.7 Metabolic Effects

There is also evidence that pentacyclic triterpenes have the potential to restore vascular disorders associated with hypertension, obesity, diabetes, and atherosclerosis, and could be used in cancer therapy, as anti-ulcer drugs, as well as for the prevention and treatment of metabolic diseases.

Oleanolic acid has antifungal, anti-inflammatory, anti-HIV, diuretic, glucose-lowering, and anticancer activities based on laboratory data.

Some triterpenes are currently being evaluated in clinical trials. Although triterpenes showed significant biological activity in in vitro assays and in some animal models, the in vivo efficacy in humans is still questioned.

Evidence assessment: Metabolic (antidiabetic, antihyperlipidemic, anti-obesity) applications are supported by animal and in vitro data. Human clinical evidence is currently sparse and insufficient to establish clinical recommendations.

5. Body Systems and Health Areas Associated with Pentacyclic Triterpenoids

Pentacyclic triterpenoids are biologically active phytochemicals having a different range of activities such as anti-inflammatory, hepatoprotective, anti-hypertensive, antiulcerogenic, and anti-tumor. This class of compounds presents several biological activities, including anti-inflammatory, antioxidant, anti-viral, anti-diabetic, anti-tumor, hepato-protective, and cardio-protective activities.

• Musculoskeletal system: Boswellic acids (AKBBA) have the most human evidence, with clinical trials demonstrating benefits in osteoarthritis of the knee, including pain reduction, improved physical function, and biomarker changes.
• Hepatobiliary system: Oleanolic acid and glycyrrhizin have demonstrated hepatoprotective properties. Oleanolic acid has been registered as a pharmaceutical agent for liver disorders in China.
• Integumentary system (skin): Centella asiatica triterpenoids (asiaticoside, madecassoside) are associated with wound healing and skin disorder applications.
• Immune and inflammatory system: Multiple compounds modulate NF-κB, COX, LOX, and related pathways; other studies have demonstrated antioxidant, antiallergic, antipruritic, antiangiogenic, and antimicrobial potential.
• Oncology: Extensive preclinical investigation; some Phase I human trials are ongoing for triterpenoid derivatives.
• Metabolic and endocrine: Antidiabetic and antihyperlipidemic effects demonstrated in animal models.
• Respiratory system: Traditional use and some in vitro antiviral evidence for licorice-derived triterpenoids; boswellic acids studied in bronchial asthma.

6. Dosage Forms and Doses Reported in Studies

Reported doses vary substantially by compound, preparation, and therapeutic area. The following are doses as reported in published studies:

• Boswellia serrata extract (BSE, osteoarthritis): 169.33 mg of extract containing 30% AKBBA, given orally twice daily for 120 days.
• Boswellia serrata extract (Boswellin® Super, osteoarthritis): Standardized extract administered for 90 days in a randomized, double-blind, placebo-controlled trial of 105 subjects.
• Boswellia serrata single-dose pharmacokinetics: A pharmacokinetic study of 11-keto-β-boswellic acid was conducted in twelve healthy male volunteers between 18 and 50 years of age after oral single dose of Wok Vel™ capsule containing standardized B. serrata gum extract with a minimum of 65% organic acids or minimum 40% total boswellic acids. A single dose administration of 333 mg of the standardized B. serrata did not cause side effects.
• Ursolic acid and oleanolic acid mixture (animal study, antitubercular drug hepatoprotection): The ursolic acid and oleanolic acid mixture at doses of 100 or 200 μg/mouse/day was subcutaneously injected throughout the entire study period of 11 weeks.
• Glycyrrhizin (SNMC preparation, hepatitis C): Intravenous administration in a clinical preparation; specific dose per injection varies by formulation and clinical protocol.

The main disadvantage of the natural pentacyclic triterpenes is their low solubility in water, and therefore, low bioavailability in physiological media. The current drawbacks preventing the promotion of these compounds into clinical practice include low biological action potential of native triterpene acids, poor aqueous solubility, and insufficient bioavailability from the gastrointestinal tract.

Asiatic acid is poorly soluble or miscible in water; it is stable in saline and dissolves at a concentration of 0.1583 mg/mL in saturated saline. Asiatic acid undergoes rapid metabolism that makes it less bioavailable.

7. Safety Considerations and Notable Interactions

7.1 Glycyrrhizin and Pseudoaldosteronism

The most clinically documented safety issue in this class is associated with glycyrrhizin from licorice root:

Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity.

Prolonged licorice consumption precipitates cortisol-induced mineralocorticoid effects, manifesting as hypoaldosteronism-like symptoms, including reduced renin levels, sodium retention, hypokalemia, elevated blood pressure, and metabolic alkalosis. Excessive ingestion of licorice can lead to hypertension, QT interval prolongation, cardiac arrhythmias, rhabdomyolysis, hypokalemia, elevated CPK levels, metabolic alkalosis, and seizures.

Pseudohyperaldosteronism due to licorice toxicity can mimic the features of primary aldosteronism without elevation of serum aldosterone concentration; electrolyte abnormalities may include hypokalemia, hypernatremia, metabolic alkalosis, and acute kidney injury; neuromuscular manifestations can include paralysis, epileptiform manifestations, altered level of consciousness, and rhabdomyolysis; cardiovascular effects can include ECG changes such as QT interval prolongation, U waves, supraventricular tachycardia, hypertension, heart failure, pulmonary edema, and cardiac death.

High dosage and long-term use of licorice are constitutional risk factors for PsA. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype.

The widespread presence of glycyrrhizin in food, beverages, and herbal products represents a growing toxicological concern.

7.2 Cytochrome P450 Inhibition and Drug Interactions

Both oleanolic acid and ursolic acid have been shown to interact with cytochrome P450 enzymes in human liver microsomes. Oleanolic acid and ursolic acid, which are noted for their hepato-protective effects, were tested for their ability to modulate the activities of several cytochrome P450 (CYP) enzymes using human liver microsomes. This inhibitory potential is significant because CYP enzymes are responsible for the metabolism of many pharmaceutical drugs; inhibition can alter plasma levels of co-administered medications.

7.3 Bioavailability Limitations and Their Consequence for Safety Evaluation

The poor aqueous solubility and insufficient bioavailability from the gastrointestinal tract of most free triterpenoid acids means that effects observed at high concentrations in vitro may not be achievable in humans at conventional supplemental doses, limiting both efficacy and certain toxicological risks. However, this same limitation means that the clinical safety profile of isolated triterpenoids at typical supplement doses remains incompletely characterized.

7.4 General Safety Profile of Boswellia serrata Extracts

With regard to the safety of Boswellia serrata, studies showed that Boswellia serrata extract (such as 5-Loxin and Aflapin) does not have toxic side effects at the doses used in clinical trials, and no serious adverse events were reported in the 120-day knee osteoarthritis trial described above.

7.5 Low Water Solubility as a Safety and Formulation Consideration

Despite the significant biological activities of pentacyclic triterpenoids, their poor water solubility and low bioavailability have limited further development and application. Advances in drug delivery technologies such as nanocarriers and targeted delivery systems have improved the bioavailability and therapeutic efficacy of triterpenoids.

7.6 Evidence Gaps

A number of potential biochemical effects of ursolic acid have been investigated, but there has been no clinical study demonstrating benefits to human health.

Although triterpenes showed significant biological activity in in vitro assays and in some animal models, the in vivo efficacy in humans is still questioned. The large body of mechanistic and animal data for most pentacyclic triterpenoids has yet to be matched by adequate numbers of well-designed human clinical trials, and regulatory approval for specific health claims remains limited outside of certain pharmaceutical applications (e.g., oleanolic acid preparations in China; glycyrrhizin preparations in Japan).

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• Pentacyclic Triterpene Bioavailability: An Overview of In Vitro and In Vivo Studies — PMC (2017)
• Ursolic Acid and Its Derivatives as Bioactive Agents — PMC (2019)
• A pilot, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of a novel Boswellia serrata extract in the management of osteoarthritis of the knee — PMC (2019)
• A standardized Boswellia serrata extract shows improvements in knee osteoarthritis within five days — Frontiers in Pharmacology (2024)
• Effectiveness of Boswellia and Boswellia extract for osteoarthritis patients: a systematic review and meta-analysis — PMC (2020)
• Efficacy and Safety of Boswellia serrata and Apium graveolens L. Extract Against Knee Osteoarthritis — PMC (2025)
• Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review — PMC (2021)
• Hypertensive crisis with target organ impairment induced by glycyrrhizin: A case report — PMC (2018)
• Pseudo-Hyperaldosteronism Arising from Licorice Cough Syrup Self-Ingestion: A Case Report — PMC (2025)
• Licorice-Induced Pseudohyperaldosteronism: A Case Report — Clinical Case Reports, Wiley (2025)
• Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism — Frontiers in Nutrition (2021)
• Mimicking Nature in Reshaping the Triterpene Skeleton — Organic Letters, ACS (2025)
• Multifunctional oxidosqualene cyclases and cytochrome P450 involved in the biosynthesis of apple fruit triterpenic acids — PMC (2016)
• Engineering amino acid residues of pentacyclic triterpene synthases for improving the activity — Applied Microbiology and Biotechnology, Springer (2024)
• Biosynthetic pathways of triterpenoids and strategies to improve their biosynthetic efficiency — PMC (2022)
• Biotransformation of Oleanane and Ursane Triterpenic Acids — PMC (2020)
• Ursolic acid — Wikipedia
• The Emerging Promise of Pentacyclic Triterpenoid Derivatives as Novel Antiviral Agents Against SARS-CoV-2 Variants — Molecules (2026)
• Pentacyclic Triterpenoids-Based Ionic Compounds: Synthesis, Study of Structure-Antitumor Activity Relationship — PMC (2023)