Introduction
Ursolic acid, also known as urson, prunol, micromerol, and malol, is a pentacyclic triterpenoid compound which naturally occurs in a large number of vegetarian foods, medicinal herbs, and plants1,2. For a long time, it was considered to be pharmacologically inactive3. Thus, ursolic acid and its alkali salts (e.g. potassium or sodium ursolates) were exclusively used as emulsifying agents in pharmaceutical, cosmetic, and food preparations3,4. However, upon closer examination, ursolic acid was found to be medicinally active both topically and internally1. Its anti-inflammatory, antitumor (skin cancer), and antimicrobial properties make it useful in cosmetic applications1.



Botanical Sources
Like most triterpenoids, ursolic acid is ubiquitous in the plant kingdom5. Ursolic acid and its derivatives are constituents of numerous plants which have diversified phylogenetic origins and taxonomic positions. It has been isolated from the protective wax-like coatings of apples, pears, cranberries, prunes, and other fruits6. Seaweeds are rich in ursolic acid derivatives6. Some of the more commonly known medicinal plants containing ursolic acid is shown in Table 16,7.

Figure 1. Structures of Ursolic and Oleanolic Acids.

Several ursolic acid derivatives, both natural and synthetic, have been reported. Novel ursolic acid derivatives, including ursane-type triterpenoid saponins, naturally occur as secondary metabolites through complex metabolic processes in different parts of the plant^5,8-12 Synthetic derivatives obtained from ursolic acid have been reported and evaluated for their pharmacological action^3,13-16.

Pharmacological Actions of Ursolic Acid
Medicinal plants containing ursolic acid have been used in folk medicine before it was known which constituents were responsible for their therapeutic effectiveness. Contemporary scientific research which led to the isolation and identification of ursolic acid revealed and confirmed that several pharmacological effects, such as antitumor, hepatoprotective, anti-inflammatory (oral and topical), antiulcer, antimicrobial, anti-hyperlipidemic, and antiviral, can be attributed to ursolic acid¹. However, its anti-inflammatory (topical), antitumor (skin cancer), and antimicrobial properties are pertinent to the cosmetic industry.


Inhibition of Tumor Promotion in Skin
Ursolic acid (UA) and oleanolic acid (OA), isolated from Glechoma hederacea, inhibited Epstein-Barr virus activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin. The inhibitory effects were evaluated for 20 weeks. Continuous application of UA and OA (41 nmol of each) before TPA-treatment (4.1 nmol) delayed the formation of papillomas in mouse skin and reduced the rate (%) of papilloma bearing mice. Both UA and OA exhibited remarkable inhibitory activity against tumor promotion, which is comparable to the known tumor inhibitor, retinoic acid (RA). Compared to either RA or OA, ursolic acid inhibited tumors more effectively after a single application before initial TPA-treatment as shown in Figure 2. This suggests that the role of tumor inhibition by UA differs from that of either RA or OA. It is suggested that pretreatment of skin with UA may inhibit the first dramatic cellular event in tumor promotion caused by TPA¹⁷.

Figure 2. Inhibition of TPA induced tumor-promotion in mouse skin by a single application of retinoic acid (RA), ursolic acid (UA), and oleanolic acid (OA).

P-Values in t-test: UA versus TPA-treatment = P < 0.01, OA versus TPA treatment = P < 0.01, and RA versus TPA-treatment = P < 0.01

Topical application of ursolic acid derived from rosemary extract inhibited TPA-induced tumor initiation and promotion, inflammation, and ornithine decarboxylase activity in mouse skin. Ursolic acid exhibited strong anti-inflammatory activity. It is even more active than carnosol, another constituent of rosemary extract. As shown in Figure 3, twice weekly application of 1 or 2 µmol of ursolic acid along with 5 nmol of TPA for 20 weeks inhibited the formation of skin tumors per mouse by 45 or 61%, respectively.

Lower doses (0.1 or 0.3 µmol) of ursolic acid had a similar inhibitory effect as the higher doses. Twice weekly topical application of 0.1, 0.3, 1, or 2 µmol of ursolic acid along with 5 nmol TPA for 8, 12, and 18 weeks reduced the number of skin tumors per mouse by 52-86%, 49-63%, and 44-61%, respectively¹⁸.

Figure 3. Inhibitory effect of ursolic acid (UA) on TPA-induced tumor

promotion in mouse skin.

Figure 3. Inhibitory effect of ursolic acid (UA) on TPA-induced tumor promotion in mouse skin

Each point represents the mean ± SE from 30 mice per group.

* means statistically different from TPA control group (P < 0.05).

Ursolic acid and its isomer, oleanolic acid have been recommended for skin cancer therapy in Japan¹⁹. Topical cosmetic preparations containing ursolic acid/oleanolic acid have been patented in Japan for the prevention of topical skin cancer²⁰. An ursolic acid/oleanolic acid ointment inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer in mice. Reportedly, 0% and 3% of mice developed cancer in 15 weeks and 30 weeks, respectively compared to 50% and 90% for the control mice²⁰.



Anti-Inflammatory Activity
Ursolic acid is a potent anti-inflammatory agent. Thus, it has been recommended for use in burn ointments⁴. It not only inhibits human leukocyte elastase (HLE), but also 5-lipoxygenase and cyclooxygenase activity^21,22. Ursolic acid (1.0 mg/ear) inhibited TPA-induced mouse ear edema by 72.4%²³. Hirota and coworkers²⁴ determined that 200 µg and 50 µg applications of ursolic acid inhibited 12-O-hexadecanoyl - 16 - hydroxyphorbol -13-acetate (HPPA)-induced inflammation by 49% and 33%, respectively. In addition, it inhibited concanavalin A (Con A) induced histamine release, which can cause severe inflammation, by 95% at a concentration of 0.001 M²⁵.

Hair Growth Stimulant
Ursolic acid and its isomer, oleanolic acid, have been used in tonics to enhance hair growth and prevent scalp irritation^26,27. Both triterpenoid compounds encourage hair growth by stimulating the peripheral blood flow in the scalp and activating the hair mother cells. They also furnish alopecia-preventing and dandruff-preventing effects²⁷.

Antimicrobial Activity
b-ursolic acid (triterpenoid sapogenin from the ursan group) inhibited the growth of several strains of stapylococci²⁸. Numerous ursolic acid containing plants from the Lamiaceae family exhibited antibacterial/fungal activity²⁹. The minimal inhibitory concentration of Rosmarinus officinalis, Origanum majorana, and Lavandula officinalis were 500, 250, and 500 µg/cm³, respectively²⁹. Ursolic acid also inhibited the growth of Microsporium lenosum and Candida albicans at 250 µg/mL³⁰.

Anti-Aging Agent
Ursolic acid treatment improves the health of skin and hair. Ursolic acid and its derivatives form oil-resistant barriers on the skin and hair as they do in the waxy coating of fruits⁶. Ursolic acid has been used to treat photoaged skin because it prevents and improves the appearance of wrinkles and age spots by restoring the skin’s collagen bundle structures and its elasticity³¹. Concentrations of ursolic acid ranging from 0.01 to 50 mg have been reported for inclusion in skin treatment preparations^32-33.

Toxicity
Notwithstanding its numerous pharmacololgical properties, ursolic acid is an ideal cosmetic ingredient because its overall toxicity (both chronic and acute) is low. It is not a primary irritant or sensitizer. In fact, it has been termed dermatologically innocuous⁴.

                                                Disclaimer
"Protocols of studies on cosmeceutical products performed /sponsored by Sabinsa Corporation are based on alternatives to animal testing. Any references to animal tests appearing in product informational materials are related to information from published scientific literature compiled therein."

References

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