Vitricin

Vitricin

Vitricin is a naturally occurring alkaloid first isolated from the fruits of Vitex trifolia L. (family Lamiaceae, formerly placed in Verbenaceae), a medicinal plant with a documented history of use across Asia and the Pacific. The compound was formally characterised and named in a 1962 paper by Döpke published in Naturwissenschaften, making it one of the earliest phytochemical constituents identified from that species. Within the broader scientific literature, vitricin is discussed in the context of the rich secondary metabolite profile of V. trifolia, a plant now the subject of comprehensive ethnopharmacological and pharmacological review.

Identity and Natural Source

Botanical Source

Vitex trifolia L. is a shrub or shrubby tree that may grow up to 6 m in height. It is found in regions of Asia, China, India, Indonesia, Sri Lanka, Singapore, and Australia. From the Verbenaceae/Lamiaceae family, it is a deciduous plant mainly found in the coastal areas of Pacific-Asian regions. It is commonly known as Panikisanbhalu (Hindi), three-leaf chaste tree (English), and 三叶蔓荆 (Chinese). Vitex trifolia L. is also known as common chaste tree (English), nochi (Kannada), and jalanirgundi (Sanskrit).

Both Vitex rotundifolia L.f. and Vitex trifolia L. belong to the genus Vitex, and V. rotundifolia L.f. evolved from V. trifolia L. The stem of V. trifolia L. is erect with 3 leaflets, while V. rotundifolia L.f. is creeping, rooting on the node, with 1 leaflet. Both are deciduous shrubs mainly distributed in East Asia, Southeast Asia, and Australia.

Chemical Identity

The plant has yielded a novel alkaloid called vitricin. The compound's original characterisation is recorded in the scientific literature as: Döpke, W. "Vitricin, ein neues Alkaloid aus Vitex trifolia Linn." Naturwissenschaften 49, 375 (1962). Translated from German, the title reads: "Vitricin, a new alkaloid from Vitex trifolia Linn." The fruits contain the alkaloid vitricin. In the broader genus Vitex, vitricin is classified as an alkaloid constituent of V. trifolia, co-occurring with other identified classes including benzofuran-type lignans, glucosides, and diterpenes of halimane, abietane, and labdane types.

It is important to note that vitricin is a minor alkaloid constituent identified from V. trifolia fruits. The overwhelming body of phytochemical and pharmacological literature on V. trifolia focuses on the plant's major secondary metabolite classes — terpenoids and flavonoids — rather than on vitricin as an isolated pharmacological entity. As a result, essentially no standalone clinical, preclinical, or mechanistic data exist for vitricin as a pure compound. The phytochemistry, traditional use, and pharmacological evidence described in this article therefore characterise vitricin in the context of its source plant and the chemical matrix in which it naturally occurs.

Co-Occurring Constituents of the Fruit Matrix

Alpha-pinene, 3,6,7-trimethylquercetagetin, Vitex trifolia compounds A–G, monoterpenes and diterpenes, dihydrosolidagenone, beta-sitosterol-3-O-glucoside, hexanic acid, and dichloromethanic acid have been recovered from the fruits of V. trifolia. Essential oils, flavones, artemetin, 7-dimethylartemetin, friedelin, and non-flavonoids and alkaloids including vitricin are found in the bark and leaves. Among sesquiterpenes, caryophyllene is the most abundant. The plant also contains palmiticacid, ethyl-p-hydroxybenzoate, 3,4-dihydroxybenzoic acid, 4-hydroxy-3-methoxybenzoic acid, caffeic acid, hydroxylethyl cinnamate, luteolin, quercetin, apigenin, casticin, and 3,6,7-trimethylquercetagetin.

Aerial parts of V. trifolia yielded friedelin, beta-sitosterol and its beta-D-glucoside, and a long-chain hydrocarbon. The leaves yielded the flavonoids artemetin, luteolin, orientin, and casticin, as well as the iridoid glycosides aucubin and agnuside.

Phytochemical analyses reveal a spectrum of secondary metabolites in V. trifolia, including terpenoids, flavonoids, lignans, phytosterols, anthraquinones, and fatty acids. Notably, terpenoids and flavonoids emerge as the main bioactive metabolites.

Forms and Preparations

The Vitex tree, including its leaves and fruits, has been used for herbal remedies in the form of pastes, decoctions, and dried fruits since ancient times. Viticis Fructus (called Manjingzi in China) is the dried ripe fruits of the plant species Vitex trifolia subsp. litoralis Steenis and Vitex trifolia L. in the family Lamiaceae. In China, the fruits of Vitex rotundifolia L.f. and Vitex trifolia L. are uniformly called Fructus Viticis and are included in the 2020 edition of the Pharmacopoeia of the People's Republic of China. The roots, stems, leaves, and fruits of various plants of this genus can be used as medicine.

Traditional and Historical Use

Traditional Chinese Medicine

The traditional use of the fruit can be traced back to ancient times, with its earliest recorded mention appearing in Shen Nong's Classic of Materia Medica of China. This historical text commended it for its medicinal properties and addressed it as a remedy for various afflictions. Among its attributed benefits, it was believed to alleviate conditions like cold and heat between the tendons and bones, address dampness impediment, enhance vision by brightening the eyes, strengthen the teeth, unblock the "nine orifices" (body openings), and eliminate taeniasis, a condition caused by tapeworm infection.

Viticis Fructus has been used as a traditional Chinese medicine for thousands of years to treat illness such as colds, headache, vertigo, anesthesia, and hyperkinesias. Dried ripe fruits of V. trifolia (also known as Fructus viticis) are well documented in Traditional Chinese Medicine to treat ailments like inflammation of the eye, headache, blurred vision, rhinitis, and common cold. Leaves of V. trifolia are also used in traditional medicine to treat inflammatory conditions, such as ciguatera fish poisoning in the Pacific region.

Indian Traditional Medicine (Ayurveda and Siddha)

Most species of the genus Vitex are used therapeutically in ancient Indian systems of medicine, especially Ayurveda and Siddha. Leaves are commonly used as poultice for rheumatic pains, in inflammations, sprains, and fever. Roots are used to treat painful inflammations, cough, and fever. Flowers are used in treating fever, and fruits in amenorrhoea. The plant is also used by local medical practitioners in treating acute jaundice.

Vitex trifolia L. is a medicinal plant traditionally used in Thai medicine for treatment of muscle pain and skin disorders.

Other Regional Traditions

In Papua New Guinea, the natives make use of the stem of V. trifolia L. to treat dysentery. Across Asia, these plants are traditionally used for the treatment of cold fever, headache, eye pain, diarrhea, dysentery, postpartum recovery, and bruises. The various species of Vitex have been used to treat a range of human ailments, particularly related to insects, fungi, bacteria, snakes and poisonous spiders, and diseases associated with menstruation and gynaecological problems.

This plant has a rich history in traditional medicine for its effectiveness in treating asthma and respiratory disorders.

Key Constituents and Phytochemistry

As noted above, vitricin is the alkaloid name given to a compound isolated from the fruits of V. trifolia, with no comprehensive standalone pharmacological characterisation currently available in the accessible peer-reviewed literature beyond its original isolation report. What is extensively documented is the full secondary metabolite profile of the plant from which vitricin derives, and the pharmacological activities of those co-occurring constituents. These are described below as context for understanding the chemical environment in which vitricin occurs.

Terpenoids (Primary Bioactive Class)

Four novel labdane diterpenoids, vitetrolins A–D, were discovered through phytochemical analysis of the ethanol extract of V. trifolia fruits. Further investigation on the isolation of V. trifolia labdane diterpenoid alkaloids led to identification of a cyano-substituted pyrrole cyclic system from the ethanolic extract of the leaf. The precursors of geranylgeranyl pyrophosphate (GGPP), ammonia, and an amino acid may contribute to the biosynthesis of these remarkable metabolites. In Vitex trifolia, the most abundant subclasses of triterpenoids identified are oleanane, ursane, and lupane types. Furthermore, a metabolite with a taraxerane structure has been identified, enhancing this species' chemical profile.

Flavonoids (Primary Bioactive Class)

Fructus Viticis comprises substantial quantities of flavonoids, including casticin, isoorientin, hesperidin, luteolin, apigenin, and isovitexin. Of these, casticin (also known as vitexicarpin or casticine) has attracted the most research attention. Casticin is a polymethylflavone with three rings, an orthocatechol moiety, a double bond, two hydroxyl groups and four methoxyl groups. It has been isolated from various tissues of plants in the Vitex genus: fruits and leaves of V. trifolia, aerial parts and seeds of V. agnus-castus, and leaves of V. negundo.

Other Constituents

Preliminary phytochemical screening of V. trifolia leaves hydroalcoholic extract showed the presence of alkaloids, flavonoids, phenols, phytosterols, and terpenoids. Qualitative testing of V. trifolia methanol extract demonstrated the presence of secondary metabolites such as steroids, saponins, alkaloids, flavonoids, terpenoids, and tannins. This plant is known to possess various active constituents including essential oil, halimane-type diterpenes, and vitetrifolins.

Pharmacological Activities of the Source Plant

Because vitricin as an isolated compound has not been the subject of standalone mechanistic or clinical study, the following section reports the documented pharmacological activities of V. trifolia as a whole and of its characterised individual constituents, in accordance with the available peer-reviewed evidence. All findings are from preclinical (in vitro or animal) models unless otherwise stated; no human clinical trials specifically evaluating vitricin as a discrete compound were identified in the literature.

Anti-Inflammatory Activity

When tested against carrageenan-induced paw oedema in rats, the hydroalcoholic extract of V. trifolia exhibited anti-inflammatory properties. A study group treated with the plant extract showed lower levels of mast cells, inflammatory mediators, and macrophages compared to animals treated with the control group indomethacin.

In a laboratory study, fresh leaves of V. trifolia were extracted using Soxhlet, ultrasonication, and maceration in hexane, dichloromethane, methanol, ethanol, or water. Each extract was evaluated for its effects on TNF-α and IL-1β cytokine production by enzyme-linked immunosorbent assay in lipopolysaccharide-stimulated human U937 macrophages.

Casticin, isolated from V. trifolia, in a dose-dependent manner at concentrations of 10, 20, and 30 μM over 2 h incubation, reduced proinflammatory cytokines such as IL-6, TNF-α, and prostaglandin E2 (PGE2), as well as oxidative stress markers including MDA and inducible nitric oxide synthase (iNOS) expression. Specifically, at 30 μM, casticin downregulated IL-6 protein expression in IL-1β-stimulated ADTC5 cells to 40 pgr/mL compared to 67 pgr/mL in the control group.

Vitrosin A and vitexicarpin, isolated from the plant, blocked spontaneous contraction of isolated guinea-pig trachea induced by histamine (Planta Med, 2002, Nov., 68/11).

In vitro assays demonstrated significant antioxidant activity in leaf extracts, with 77.85% DPPH radical scavenging at 100 µg/mL and 73.33% nitric oxide radical scavenging at 1000 µg/mL. The extracts also exhibited potent antidiabetic effects, inhibiting α-amylase by 67.25% at 100 µg/mL, and strong anti-inflammatory activity, with 70.25% inhibition of albumin denaturation at 800 µg/mL.

Evidence strength: Preclinical only (cell culture and animal models). No human clinical trials are available.

Analgesic Activity

Vitex trifolia has been used in traditional medicine for pain relief in conditions like inflammation and rheumatism. Animal studies, including acetic acid-induced writhing and tail-flick tests, have shown that its analgesic activity is comparable to that of diclofenac sodium, suggesting its potential as a natural pain reliever, particularly for inflammatory pain.

To evaluate the in vivo analgesic and anti-inflammatory activities of the ethanolic extract of V. trifolia (VTE), analgesic activity was assessed using acetic acid-induced writhing and hot plate tests, and anti-inflammatory activity was assessed using ethyl phenylpropiolate (EPP)-induced ear edema and carrageenan-induced paw edema models in rats. The findings provided pharmacological and formulation-based evidence supporting its traditional use, highlighting its potential as a standardized herbal product for inflammatory skin conditions.

Vitex trifolia may modulate excitatory neurotransmitter pathways, possibly by interacting with glutamate receptors or inhibiting glutamate neurotransmission. The significant analgesic activity observed through both peripheral and central mechanisms indicates that V. trifolia may serve as a potential natural analgesic, particularly for treating inflammatory and neuropathic pain.

Evidence strength: Preclinical only. No human clinical trials are available.

Antioxidant Activity

Vitex trifolia has high concentrations of phenols, alkaloids, flavonoids, and saponins, all of which have antioxidant properties. Phytochemical analysis of the leaf extracts revealed high levels of total phenolics (95.12 mg GAE/g) and flavonoids (42.50 mg QE/g). Under DPPH radical scavenging activity, the IC50 value of V. trifolia hydroalcoholic leaves extracts was found to be 70.57 µg/mL compared to ascorbic acid.

Evidence strength: In vitro preclinical only.

Hepatoprotective Activity

Results of serum biochemical estimations revealed significant reduction in total bilirubin and serum marker enzymes, and increase in total protein, in animals treated with ethanol and aqueous extracts. The hepatoprotective activity was also supported by histological studies of liver tissue; histology of the liver tissue treated with extracts showed normal hepatic architecture with few fatty lobules. The study revealed that Vitex trifolia could afford significant protection against CCl4-induced hepatocellular injury. The plant extract showed significant hepatoprotective activity at a dose of 200 mg/kg.

Casticin, one of the flavonoids extracted from Viticis Fructus, can reduce the expression of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 resulting from blocking TGF-β1/Smad signaling, as well as increase the apoptosis of hepatic stellate cells.

Evidence strength: Animal models only. No human clinical trials are available for V. trifolia hepatoprotective effects.

Anticancer / Cytotoxic Activity

Endowed with diterpenes and flavonoids as major constituents, V. trifolia has demonstrated hepatoprotective, anti-inflammatory, analgesic, and other pharmacological activities. Casticin or vitexicarpin isolated from V. trifolia displays potent cytotoxicity against a wide range of cancer cell lines via different modes of molecular action.

Isolated from the leaves of V. trifolia, casticin at 100 µg/mL concentration inhibited the proliferation of mouse tsFT210 cancer cells, with an IC50 value of 0.3 µg/mL. Casticin was also reported to inhibit the proliferation of A2780 (19 µmol/L), HCT-15 (0.7 µmol/L), HT-1080 (0.4 µmol/L), and K562 (0.3 µmol/L) human cancer cells.

The extracts of hexane and dichloromethane from the stems and leaves of V. trifolia have been shown to be highly toxic to several cancer cell lines in culture (SQC-1 UISO, OVCAR-5, HCT-15 COLADCAR, and KB). The cytotoxic activity of ethanol extract isolated from V. trifolia subsp. litoralis was analyzed by MTT method; the ethanol extract can inhibit the proliferation of human liver cancer cell line HepG2 in vitro, showing that the extract has a certain cytotoxic activity.

Evidence strength: In vitro cell-line and animal studies only. No clinical trials in human cancer patients have been reported for V. trifolia extracts or its constituents.

Antimicrobial Activity

Vitex trifolia leaf extracts showed febrifuge, antibacterial, anthelmintic, and cytotoxic properties. Extract of the leaves showed inhibitory action against Mycobacterium tuberculosis. The inhibitory test of methanol extract of roots, stems, and leaves of V. trifolia against pathogenic bacteria (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Klebsiella pneumoniae) has been carried out.

Evidence strength: In vitro preclinical only.

Antispasmodic / Respiratory Activity

The plant has a rich history in traditional medicine for its effectiveness in treating asthma and respiratory disorders. Vitrosin A and vitexicarpin, isolated from the plant, blocked spontaneous contraction of isolated guinea-pig trachea induced by histamine (Planta Med, 2002, Nov., 68/11).

Evidence strength: Ex vivo (isolated tissue) model only.

Wound Healing

The potential for wound healing was examined in the ethanol leaf extracts of Vitex altissima and Vitex trifolia. Both extracts had notable wound-healing efficacy. Vitex trifolia demonstrated optimum healing activity by showing shorter epithelization times and increased wound contraction.

Evidence strength: Animal experimental models only.

Mechanisms of Action

As with evidence for pharmacological activity, documented mechanisms relate to the whole plant extract and to individually characterised co-constituents rather than to vitricin itself as a pure compound.

• Cytokine modulation: Casticin, in a dose-dependent manner, reduced proinflammatory cytokines including IL-6, TNF-α, and prostaglandin E2 (PGE2), as well as oxidative stress markers including MDA and inducible nitric oxide synthase (iNOS) expression.
• Histamine antagonism: Vitrosin A and vitexicarpin, isolated from the plant, blocked spontaneous contraction of isolated guinea-pig trachea induced by histamine.
• Hepatic fibrosis modulation: Casticin can reduce the expression of matrix metalloproteinase (MMP)-2, MMP-9, TIMP-1, and TIMP-2 resulting from blocking TGF-β1/Smad signaling, and increased the apoptosis of hepatic stellate cells.
• Alpha-glucosidase inhibition: Extracts exhibited potent antidiabetic effects, inhibiting α-amylase by 67.25% at 100 µg/mL.
• Antiproliferative signaling: Diterpenoids and triterpenoids found in the Vitex genus exhibit anti-proliferative properties, cytotoxic activity, and have demonstrated a dopaminergic effect.
• Glutamatergic pain modulation: Vitex trifolia may modulate excitatory neurotransmitter pathways, possibly by interacting with glutamate receptors or inhibiting glutamate neurotransmission.

Body Systems and Health Areas

Pharmacological studies have validated the therapeutic potential of V. trifolia by demonstrating significant antioxidant, anti-inflammatory, hepatoprotective, anticancer, anti-amnesic, antimicrobial, antiviral, anti-malaria, and antispasmodic activities. The body systems documented in both traditional use and preclinical research include:

• Musculoskeletal system: Leaves used as poultice in rheumatism, inflammations, and sprains.
• Hepatic / Digestive system: Studies revealed that Vitex trifolia could afford significant protection against CCl4-induced hepatocellular injury.
• Respiratory system: The plant has a rich history in traditional medicine for its effectiveness in treating asthma and respiratory disorders.
• Nervous system: The leaves are reported to improve memory and favour hair growth.
• Reproductive system: Fruits have been traditionally used in amenorrhoea.
• Immune / Infectious: Extract of the leaves showed inhibitory action against Mycobacterium tuberculosis.

Dosage Forms and Doses Reported in Studies

No standardised dosage forms or dosage regimens for vitricin as an isolated pure compound have been reported in the accessible peer-reviewed literature. The following doses relate to V. trifolia preparations studied in preclinical research:

• Hepatoprotective activity of the plant extract in animal studies was reported at a dose of 200 mg/kg.
• In vitro antioxidant studies used leaf extract concentrations of 100 µg/mL and 1000 µg/mL.
• In vitro casticin studies used concentrations of 10, 20, and 30 μM for anti-inflammatory endpoints, with significant toxicity noted at 40 μM.
• In antiproliferative studies, casticin at 100 µg/mL achieved an IC50 of 0.3 µg/mL against mouse tsFT210 cancer cells.

No human clinical dose-ranging or pharmacokinetic studies for vitricin or for Viticis Fructus standardised extracts were identified in the reviewed literature.

Safety Considerations

Casticin, a flavonoid co-isolated from V. trifolia, demonstrated anti-inflammatory and antitumor effects on ADTC5 cells; however, it exhibited significant toxicity at a concentration of 40 μM after 2 h of treatment. This concentration-dependent toxicity observed in cell culture underscores the importance of dose characterisation for individual constituents of this plant.

Despite existing literature exploring pharmacological attributes and secondary metabolites of related species, a conspicuous gap exists specifically focusing on the pharmacological activities and novel methods of purification of pure metabolites from V. trifolia. Consequently, the full toxicological profile of vitricin as an isolated compound remains incompletely characterised in the publicly available scientific literature.

Interactions of Vitex-derived compounds with medications such as sedatives and blood pressure drugs are possible but poorly documented.

Documented pharmacological studies demonstrate activities spanning antioxidant, anti-inflammatory, hepatoprotective, anticancer, anti-amnesic, antimicrobial, antiviral, anti-malaria, and antispasmodic properties; however, these are derived from in vitro and animal models, and the safety implications for human use have not been established through controlled human trials.

State of Research and Evidence Summary

Vitricin, as a named alkaloid from Vitex trifolia, was first reported in the scientific literature in 1962. Since then, the primary focus of research on this species has been on the terpenoid and flavonoid fractions — particularly casticin, vitexicarpin, and various labdane diterpenes — while vitricin itself has not been the subject of isolated mechanistic, pharmacokinetic, or clinical study. Further research into mechanisms of action and optimal dosing remains essential.

Despite existing literature exploring pharmacological attributes and secondary metabolites of related species, a conspicuous gap exists specifically focusing on the pharmacological activities and novel methods of purification of pure metabolites from V. trifolia. All pharmacological evidence currently supporting interest in V. trifolia and its constituents derives from preclinical (in vitro and animal) models, with no published randomised controlled trials or systematic clinical reviews specifically addressing V. trifolia preparations or vitricin in human subjects identified in the peer-reviewed databases searched.

References

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• J-GLOBAL / JST: Article record for "Vitricin, ein neues Alkaloid aus Vitex trifolia Linn." (Döpke, 1962).