Botanicals in Skin Care Products

Review

Botanicals in skin care products Inja Bogdan Allemann, MD, and Leslie Baumann, MD

From the University of Miami Cosmetic Group, Leonard M. Miller School of Medicine, Miami Heart Institute, Miami Beach, Florida Correspondence Leslie Baumann, MD University of Miami Cosmetic Group, Leonard M. Miller School of Medicine, Miami Heart Institute, 4701 N. Meridian Avenue, Nichol Bldg., Suite 7450, Miami Beach, FL 33140 E-mail: lbwork@derm.net

Introduction In recent years, complementary and alternative medicine, together with their various practices, have become increasingly popular and even considered a highly acclaimed disciplineintheWesternworld.Botanicals,whichbydefinition are plant-derived products, play a pivotal role within the market for natural healing. In 2002, one-third of the adult US population was estimated to have used alternative medical therapies, and, in 2003, one-quarter of the adult population reported using herbs to treat a medical condition.1,2 Botanicals and the art of herbal medicine are extremely ancient, and have been used in various cultures for centuries, representing the earliest medications used by humans. The current popularity of botanical products has occurred for several reasons, and is based on a greater public access to health information, which has led to the questioning of the approaches and assumptions of allopathic medicine and concerns about the adverse effects of chemical drugs. In contrast, the notion of botanical sources is translated by patients into a ‘‘natural’’ source, which they associate with safety.

The plant kingdom offers an abundant source of substances and, in order to identify new and more potent agents with promising indications to ultimately provide novel cures for diseases, scientists have searched and are searching the flora in remote places of the world. Consequently, new as well as established and well-known botanical ingredients are added to various productson aconstant basis.

Several of the available products derived from botanical sources have been touted for their dermatologic benefits. ª 2009 The International Society of Dermatology

Herbal ingredients are used for dermatologic purposes as oral dietary supplements or incorporated into topical formulations.

Many botanicals incorporated into skin care products are referred to as cosmeceuticals, a term first introduced by Albert Kligman two decades ago.3 Cosmeceuticals are defined as intermediary substances between drugs and cosmetics, and, as such, do not require Food and Drug Administration (FDA) approval before being marketed. Unfortunately, this has paved the way for a paucity of controlled clinical trials demonstrating the effectiveness of the various active herbal ingredients.

Consequently, most of the botanical substances discussed below lack large-scale, prospective, randomized, blind, controlled clinical trails to assess their actual biologic effects.

Thus, within the vast array of botanical ingredients incorporated into skin care products, it is sometimes difficult to choose which ones truly deliver what they promise.

Adiscussionofallthecurrentlyavailablebotanicalingredients used in dermatology and dermatologic formulations would far exceed the scope of this article. Therefore, it focuses on a select group of the most popular botanical compounds includedor warranting inclusionindermatologic formulations intended for predominantly aesthetic purposes. Items selected to be discussed and reviewed below were based on a questionnaireobtainedatarecentdermatologyadvisoryboardmeeting, where dermatologists were asked which botanical ingredients they wanted to know more about. Furthermore, the methods used to select the botanicals discussed below, as well as their respective references, were MEDLINE or scholar.google.com searches for the various botanical ingredient names and words such as topical, skin, skin care, aging, pigmentation, antiaging, inflammation, and free radicals. Extensive files of International Journal of Dermatology 2009, 48, 923–934

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botanical publications at the University of Miami were used inaddition.Itisthe goalofthisarticletodiscussthe information reported on botanical ingredients for skin care formulations, not to evaluate the quality of the various reports. All papers found on MEDLINE that were pertinent were included. No paperswereexcludedonthebasisofthestudydesign.

Botanicals Obtaining a botanical to finally incorporate into a product is a highly complex process, influenced by various factors. A single plant may contain hundreds of various chemicals and active compounds. The part of the plant to represent the source from which the botanical extract is harvested is therefore crucial and can include the fruits, leaves, roots, bark, flowers, stems, and berries. The respective extracts from these partsmayallpossessvaryingchemicalconstituents.Furthermore, seasonal and climatic conditions, as well as the amount ofwater available,areadditionalfactors that influence the quality of an extracted herbal substance. Once the extract is obtained, the chemical characterization of a botanical can be difficult, as more than 200 individual chemicals may be present in one singleplantextract.

Before botanicals can be incorporated into a topical product, they must undergo numerous chemical processing steps, which greatly influence the final outcome of the botanical extract to be formulated. Ultimately, the efficacy of the plant extract added to a topical preparation depends on its concentration.

Sometimes the botanical is added in such small amounts that it provides more marketing than skin benefit.

As plants have adjusted over centuries or millennia to an environment with constant oxidative assault and damage, many botanicals exhibit strong antioxidant activities. Nevertheless, most botanicals possess various effects and often display several simultaneously, such as antioxidant, anti-inflammatory, anticarcinogenic, and pigment-lightening activity (Table 1).

Lycopene

Lycopene is a red carotenoid pigment found in red fruits and vegetables, such as tomatoes, watermelon, pink grapefruit, and apricots. Lycopene is responsible for the red color in these fruits and vegetables.4 The capacity of lycopene to quench singlet oxygen is stronger than that of a-tocopherol or bcarotene because of the large number of conjugated double bonds.5 In synergy with other nutrients, lycopene has been shown to decrease biomarkers of oxidative stress and carcinogenesis.6 In addition to its antioxidant activity, lycopene has been demonstrated to possess anticarcinogenic properties in various tumors.7,8 Withregardtoskincancer,lycopene has beenshown to exert chemopreventive effects against photoinduced tumors in mice.9 Despite a paucity of clinical data in humans, lycopene can be found in various over-the-counter skin care products, International Journal of Dermatology 2009, 48, 923–934

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Table 1 Activities of Botanicals Botanical

Biologic activity

Lycopene

Antioxidant Anticarcinogenic Antioxidant Anti-inflammatory Anticarcinogenic Antioxidant Antioxidant Anti-inflammatory Antioxidant Anti-inflammatory Antiproliferative Antioxidant Anti-inflammatory Wound healing Antimicrobial Antioxidant Anticarcinogenic Antioxidant Antiviral Antioxidant Anticarcinogenic Antioxidant Anticarcinogenic Depigmentation Anti-inflammatory Wound healing Antioxidant Anticarcinogenic Depigmentation Antioxidant Anticarcinogenic Anti-inflammatory Depigmentation Antioxidant Anti-inflammatory Anticarcinogenic Depigmentation Anti-inflammatory Hydrating Depigmentation Depigmentation Depigmentation Antioxidant Anticarcinogenic

Silymarin

Coffea arabica and Coffeeberry Polypodium leucotomos extract Resveratrol

Turmeric/curcumin

Grape seed extract Pomegranate Genistein Vitamin C

Vitamin E

Green tea

Pycnogenol

Oatmeal Aloesin Arbutin Soy proteins

including facial moisturizers, sunscreens, eye creams, and ‘‘antiaging’’ skin care.

Silymarin

Silymarin is a polyphenolic flavonoid or flavonolignan compound that can be extracted from the seeds of the milk thistle plant Silybum marianum. For over 2000 years milk thistle has been used for medicinal purposes. Today, it is used clinically inEuropeandAsiaasanantihepatotoxicagent,andisavailableas a supplement in Europe and the USA. Silybin (silibinin) is ª 2009 The International Society of Dermatology

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the key component, with antioxidant, anti-inflammatory, and anticarcinogenic properties.10 Researchers have demonstrated photoprotective effects of topically applied silybin prior to, or immediately after, ultraviolet (UV) irradiation. They showed a reduction in thymine dimer-positive cells and an up-regulation of p53-p21/Cip1, which they believe may ultimately inhibit cell proliferation and apoptosis, suggesting that mechanisms other than sunscreen effects are integral to the efficacy of silybin against UV-induced skin damage.11 Furthermore, silymarin exerts chemoprotective activity against skin cancer.12 The prevention of UV-B-induced immunosuppression and oxidative stress by the topical application of silymarin seems to be potentially related to the prevention of photocarcinogenesis in mice.13 Thus, the inclusion of silymarin into sunscreen is supported by sound scientific data. Silymarin is included in various antiaging, moisturizing, and sun-protective skin care products, as well as in topical formulations for the treatmentofrosacea.

Coffea arabica and coffeeberry extract

Coffeaarabica,aplantoriginatingfromEthiopia,isthesource of the globally consumed coffee beverage. The extracts obtained from roasted beans of the coffee plant have been shown to possess antioxidant activity.14 It is not only the coffee beans that exhibit biologic activity, however, but also the fruit of the coffee plant, which, especially when harvested in a subripened state, possesses antioxidant activity. This biologic effect is a result of the presence of polyphenols, especially chlorogenic acid, condensed proanthocyanidins, quinic acid, and ferulic acid. Coffeeberry is the proprietary name for the antioxidant, which is extracted from the fruit of the C. arabica plant. A recent study has demonstrated a higher antioxidant activity for Coffeeberry than for green tea, pomegranate extract, and vitamins C and E, as measured by the oxygen radical absorbance capacity assay.15 The first product containing coffeeberry polyphenols in a 1% concentration was launched in 2007. Clinical studies assessing the antioxidant effects of topical preparations containing C. arabica and Coffeeberry in humans are now needed. Finally, caffeine extracted from the leaves of the C. arabica plant is used in some formulations totreatcellulite.16 Polypodium leucotomos extract

Polypodiumleucotomosextractisderivedfromthefernfamily.It contains polyphenols, the major components of which are 3,4-dihydroxybenzoicacid,4-hydroxybenzoicacid,vanillicacid, caffeic acid, 4-hydroxycinnamic acid, 4-hydroxycinnamoylquinic acid, ferulic acid, and five chlorogenic acid isomers.17 In traditional medicine, P. leucotomos extract has been used to treat various medical and dermatologic conditions, such as vitiligo,atopicdermatitis,andpsoriasis.18 Several in vitro and in vivo studies have demonstrated the antioxidant effects of P. leucotomos extract, as well as its ª 2009 The International Society of Dermatology

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ability to prevent photoaging.19 Orally as well as topically administered P. leucotomos extract has been shown to possess photoprotective effects in vivo and in vitro by the inhibition of free radical generation, prevention of the photodecomposition of both endogenous photoprotective molecules and DNA, and prevention of UV-induced cell death.20 Taken orally, P. leucotomos extract has been shown to decrease sunburn and UV-induced mast cell infiltration in the skin, and reduce the loss of epidermal Langerhans cells of the skin associated with UV exposure.21 In another study supporting the photoprotective effects of P. leucotomos extract, 26 patients suffering from polymorphic light eruption and two with solar urticaria were exposed to sunlight with oral supplementation of 480 mg/day of P. leucotomos extract. The response of the skin to sunlight was compared with that occurring previously without the administration of P. leucotomos extract. There was a statistically significant decrease in skin reaction and subjective symptoms.22 In vitro studies have shown that the molecular mechanisms involved seem to suggest an inhibition of UV-light-induced tumor necrosis factor-a, nitric oxide production, and inducible nitric oxide synthase up-regulation, and a modulation of the transcriptional activation of activator protein-1 and nuclear factor-jB. Furthermore, topical application or oral administration of P. leucotomos extract in humans has been shown to exert photoprotective effects by preventing acute sunburn and psoralen-induced phototoxic reactions.23 Thus, this tropical plant extract seems to have found potential clinical applications for the treatment of sunburn, the inhibition of phototoxic reactions, and the prevention of photoaging.24 Currently, in the USA, P. leucotomos extract is available as an oral supplement for sun protection, and should be taken 1 h prior to sun exposure in conjunction with a broad-spectrum sunscreen. Polypodium leucotomos extract is included in only a few sunscreen and antiaging products.

Resveratrol

Resveratrol (trans-3,5,4¢-trihydroxystilbene), a polyphenolic phytoalexin compound, can be extracted from the skin and seeds of grapes, berries, red wine, and other foods. There are twoisoforms:themorestabletrans-resveratrolandcis-resveratrol. Resveratrol exerts strong antioxidant, anti-inflammatory, and antiproliferative activities.25,26 Resveratrol seems to exhibit chemopreventive and antiproliferative activity against various cancers, including skin cancer, as shown in in vitro and in vivo studies. The mechanisms involved seem to include an inhibition of cellular events associated with tumor initiation, promotion and progression and the triggering of apoptosis in such tumor cells.27 A decrease in UV-B-induced tumor incidence and a delay in the onset of skin tumorigenesis by the topical application of resveratrol (both pre- and posttreatment)havebeendemonstratedinlong-termstudies.28 In mice, topical application of resveratrol prior to irradiation has been shown to protect against UV-B-mediated cutaneous International Journal of Dermatology 2009, 48, 923–934

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damage. Photoprotection is manifested by a significant decrease in UV-B-mediated generation of hydrogen peroxide and infiltration of leukocytes, and the inhibition of skin edema as well as lipid peroxidation, a marker of oxidative stress.29 In vitro pretreatment of normal human keratinocytes with resveratrol resulted in an inhibition of UV-B-induced activation of the nuclear factor-jB pathway.30 The application of resveratrol post-treatment demonstrated equal protection to application pretreatment, suggesting that the responses mediated by resveratrol may notbe sunscreen effects.

Resveratrol is included in various skin care products, including facial moisturizers, antiaging creams, sunscreens, and eye creams.

Turmeric/curcumin

Turmeric (Curcuma longa Linn) belongs to the Zingiberaceae family, and is a well-known and frequently used spice in Indian cuisine, particularly in curry and prepared mustard. It has a long history in traditional, especially Ayurvedic and Chinese, medicine, and has been used for centuries for the treatment of various diseases. Curcumin (diferuloylmethane) is the yellow pigment that corresponds to the key biologically active component of turmeric, and can be extracted from the root of the tropical plant. The polyphenols contained in the curcuminoids of the turmeric tubers are strong antioxidants.

Curcumin has been shown to be a potent scavenger of reactive oxygen species, including hydroxyl radicals, superoxide anion radicals, and nitrogen dioxide radicals.31 Furthermore, it has been demonstrated to possess beneficial effects against chemoand photocarcinogenesis in several tumor model systems, including skin neoplastic models.32,33 Whether the topical application or oral intake of curcumin can inhibit skin carcinogenesis in humans has yet to be determined.34 As with many other antioxidants, curcumin also possesses antiinflammatorypropertiesbydown-regulating the production of the pro-inflammatory cytokines interleukin-1 and tumor necrosis factor-a, and inhibiting the activation of the transcription factors nuclear factor-jB and activator protein-1.35 In a study from the 1970s, curcumin was shown to possess a superioranti-inflammatoryactivitytoibuprofen.36 Finally, curcumin exerts wound-healing and antimicrobial activities.37 Currently, only a few cosmetic moisturizing and antiaging products contain curcumin, as its smell and color make it difficult to formulate into a cosmetically elegant product.

Grape seed extract

The grape, also known as Vitis vinifera, and its most popular extract, wine, have been consumed all over the world for centuries. The extract that is prepared from the seeds of grapes is rich in polyphenolic proanthocyanidins.38,39 These compounds exhibit a wide range of biologic, pharmacologic, chemoprotective, and antioxidant activities.40 Proanthocyanidins, International Journal of Dermatology 2009, 48, 923–934

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which belong to the flavonoid family, are potent free radical scavengers that can also be found in many other foods, such as various berries (e.g. strawberry, cranberry, bilberry, and blueberry), green and black tea, red wine, and red cabbage.41 The extract from grape seeds seems to have an even stronger antioxidant activity than vitamins C and E. Taken orally, grape seed proanthocyanidins have been shown to prevent UV-induced skin cancer in mice, as demonstrated by a reduced tumor incidence, multiplicity, and size after UV-B irradiation when compared with non-grape seed proanthocyanidin-treated mice. Photoprotection by grape seed proanthocyanidins in mice seems to be exerted via an antioxidant mechanism by the inhibition of UV-B- or Fe3+induced lipid peroxidation.42 In vitro treatment of normal human keratinocytes with grape seed proanthocyanidins results in an inhibition of UV-related oxidative stress by impeding UV-B-induced hydrogen peroxide, lipid peroxidation, protein oxidation, and DNA damage, and scavenging hydroxyl radicals and superoxide anions. In addition, the UV-Binduced depletion of endogenous antioxidant defense enzymes, such as superoxide dismutase, peroxidase, catalase, and glutathione, can be inhibited by grape seed proanthocyanidins. Finally, grape seed proanthocyanidins have been demonstrated to modulate the mitogen-activated protein kinase and nuclear factor-jB signaling pathways, both activated by UV-induced oxidative stress, thus protecting the skin from the adverse effects of UV-B radiation in an animal model.43 The oral intake of grape seed proanthocyanidins has been shown to reduce the production of the immunosuppressive cytokine interleukin-10 and enhance the production of the immunostimulatory cytokine interleukin-12, thus modulating UV-B-induced immunosuppression in mice.44 The topical application of grape seed extract has been demonstrated to enhance the sun protection factor in humans.

Various topical cosmetic formulations contain grape seed extract, mainly for antiaging effects.

Pomegranate

Pomegranate (Punica granatum) is a well-known edible fruit and fruit juice originating from Persia, and now widely cultivated. Interestingly, it was one of the first known sources of ancient medicines, and many cultures around the world have used it to treat various diseases. In Ayurvedic medicine, pomegranates are believed to restore balance to the skin.

Extracts can be obtained from the fruit itself, the seeds, and the peel, and all exhibit potent antioxidant activities, especially the phenolic components.45,46 The fruit extract contains two types of polyphenol: anthocyanins (e.g. delphinidin, cyanidin, and pelargonidin) and hydrolyzable tannins (e.g. punicalin, pedunculagin, punicalagin, and gallagic and ellagic acid esters of glucose). In a recent study, the antioxidant potency of various beverages known to be rich in polyphenols was compared using four different tests. Compared with red wine, ÂŞ 2009 The International Society of Dermatology

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black, green, and white tea, as well as various fruit juices (including apple, açaí, black cherry, blueberry, cranberry, and orange), pomegranate juice showed the strongest antioxidant potency, with at least a 20% greater potency than any of the other beverages tested.47 In other studies, pomegranate has displayed stronger antioxidant activity when compared with similar quantities of green tea and red wine.48,49 Topical application of pomegranate also imparts antioxidative effects by restoring catalase, peroxidase, and superoxide dismutase enzyme activities in rats.50 Moreover, pomegranates possess anticarcinogenic activities, as shown in vitro and in vivo.51 The oil that can be extracted from the seeds possesses chemopreventive effects against skin cancer.52 The fruit extract is also photochemopreventive, modulating cellular pathways that ameliorate UV-A-mediated damage.53 When applied topically in a CD-1 mouse model of chemical carcinogenesis, the fruit extract was demonstrated to possess skin tumor-suppressing effects.54 In normal human keratinocytes, pomegranate fruit extract has been shown to inhibit UV-B-induced modulations of nuclear factor-jB and mitogen-activated protein kinase pathways.55 In human immortalized HaCaT keratinocytes, pretreatment with pomegranate fruit extract before UV-B irradiation inhibited the UV-B-mediated decrease in cell viability and intracellular glutathione content, the increase in lipid peroxidation, and the up-regulation of various matrix metalloproteinases and phosphorylation of mitogen-activated protein kinases.56 Other in vitro studies suggest that the peel fractions of pomegranate may increase dermal regeneration, whereas seed oil fractions may promote epidermal regeneration.57 Numerous over-thecounter skin care products contain pomegranate.

Genistein

Genistein (4¢,5,7-trihydroxyisoflavone) is an isoflavone first isolatedfrom soybeansin1931.58 Asians,who arewell known to have a high consumption of soy, exhibit significantly lower incidences of various cancers, including colon, breast, and prostate, compared with individuals from other continents.

Such health benefits have been at least partly attributed to soy.59 Its anticarcinogenic effects are well documented in several cancers, including the skin.60,61 As a potent antioxidant, genistein has been shown to inhibit UV-induced oxidative DNA damage and to block UV-induced c-fos and c-jun proto-oncogene expression in vitro and in vivo.62,63 Furthermore, it has been demonstrated to substantially block the subacute and chronic UV-B-induced cutaneous damage and histologic alterations related to photoaging in mice.61 In humans, pre-UV-B exposure application of genistein has been showntoeffectivelyprotecttheskinagainstUV-B-inducedskin photodamage. From these data, the soybean isoflavone seems to have promising implications in the prevention of UVinduced skin cancer and photoaging. Genistein is already included in various products, such as sunscreens, facial ª 2009 The International Society of Dermatology

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moisturizers, and several products touted as imparting an antiaging effect.

Vitamin C

By the 18th century, the ingestion of citrus fruits was known to prevent scurvy. In the 1930s, researchers confirmed that vitamin C was the key ingredient in citrus fruit, responsible for the prevention of scurvy. Unlike other mammals that require it, humans cannot internally produce vitamin C, also known as ascorbic acid, and must obtain it from food, such as citrus fruits, blackcurrants, red peppers, and leafy green vegetables. The oral supplementation of vitamin C, however, does not increase the levels of vitamin C in the skin, because of limited transport capacity from the gastrointestinal tract.

Moreover, sunlight and environmental pollution deplete epidermal vitamin C.64,65 As vitamin C is known to be a strong antioxidant, enhancing its levels in the skin is of great importance.

Vitamin C has been shown to interfere with the UV-induced generation of reactive oxygen species by reacting with superoxide anions or hydroxyl radicals, and has consequently been added to ‘‘after-sun’’ products.66 In animal models, the topical application of vitamin C has been shown clinically to yield photoprotective effects by the demonstration of a significant decrease in erythema and tumor formation, and, histologically by a reduction in sunburn cells, after both UV-A and UV-B irradiation.67,68 Furthermore, the topical application of vitamin C combined with either a UV-A or UV-B sunscreen results in improved sun protection when compared with sunscreen alone.69 Vitamin C also amplifies the antioxidant capacities of vitamin E by reducing oxidized vitamin E back to its active form.70 In addition to scurvy, which results from the prolonged lack of vitamin C, deficiency of ascorbic acid leads to impaired collagen production, as ascorbate acts as a cofactor for the enzymatic activity of prolyl hydroxylase, an enzyme that hydroxylates prolyl residues in procollagen, elastin, and other proteins with collagenous domains prior to triple helix formation, thus playing an important role in collagen synthesis.71 The addition of ascorbic acid to fibroblast cultures has been demonstrated to increase collagen production.72 Although stimulating collagen biosynthesis, however, some studies have shown vitamin C to act as an antagonist to elastin accumulation.73,74 Currently, the clinical significance of the possibility of an adverse effect of vitamin C on elastin production is unclear.

In humans, vitamin C applied topically over a 3-month period has been shown to significantly decrease wrinkles relative to the untreated side, assessed by photography and optical profilometry.75 In another double-blind, randomized trial, healthy females topically applied cream containing 5% vitamin C to their photoaged faces over a 6-month period.

A statistically significant improvement in wrinkles, brown International Journal of Dermatology 2009, 48, 923–934

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spots, hydration, and glare was demonstrated. In addition, ultrastructurally elastic tissue repair was documented, and tissue levels of the inhibitor of matrix metalloproteinase-1 were shown to be increased, reducing UV-induced collagen breakdown.76 In addition to its antioxidant activities, vitamin C acts as an anti-inflammatory agent. As vitamin C inhibits melanin formation and reduces oxidized melanin by reducing odopaquinone back to dopa, thus avoiding melanin formation, it is also used as a depigmentation agent.77 Iontophoresis seems to enhance the penetration of vitamin C into the skin, and has consequently been shown to significantly decrease pigmentation compared with placebo in a randomized, double-blind, placebo-controlled study.78 As it has not yet been demonstrated that the ingestion of vitamin C leads to increased levels of vitamin C in the skin, topical vitamin C preparations have become popular. Nevertheless, the penetration of vitamin C through the stratum corneum poses a challenge, and many of the currently available topical preparations fail to penetrate the barrier and are therefore useless. A further problem with the formulation of vitamin C into a topical product is its lack of stability. When exposing vitamin C preparations to UV rays or air, the molecule adds two electrons and converts to a new substance, dehydro-L-ascorbic acid, which contains an aromatic ring.

This substance can be reduced back to ascorbate; however, if further oxidized, the ring irreversibly opens, forming diketogulonic acid, and the vitamin C solution becomes permanently inactive.79 Therefore, airtight containers with UV protection are an absolute requirement. Two companies have succeeded in developing stabilized vitamin C preparations, packaged in a manner intended to minimize the inactivation of this easily degraded product. When applied topically, a small number of patients have reported a stinging sensation and general minimal discomfort. It makes sense to supplement vitamin C orally, so as to benefit from its antioxidative effects in the arteries, liver, and other amenable organs.

Vitamin E

Vitamin E, or tocopherol, can be found in various foods, including vegetables, such as asparagus and spinach, seeds, nuts, and olives. Vitamin E is the universal term for eight related tocopherols and tocotrienols. Of the four tocopherols (a-, b-, c-, and d-), a-tocopherol has the highest activity and bioavailability and, consequently, has been most extensively studied. The forms of vitamin E are referred to as either ‘‘tocopherol’’ or ‘‘tocopheryl,’’ followed by the name of the attachment, e.g. ‘‘tocopheryl acetate.’’ Both forms are similar, but tocopherol exhibits better absorption, and tocopheryl possesses a slightly longer shelf-life. Oral forms of vitamin E sold in health food stores are mostly D-a-tocopherol, D-atocopheryl acetate, and a-tocopheryl succinate. The vitamin E forms typically used in cosmetics are a-tocopheryl acetate International Journal of Dermatology 2009, 48, 923–934

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and a-tocopheryl linoleate. These compounds are less likely than D-a-tocopheryl to elicit contact dermatitis, and are more stable at room temperature.

Elderly subjects exhibiting high plasma tocopherol levels have been shown to exhibit a lower incidence of infectious diseases and cancer; dietary deficiency of vitamin E has been demonstrated to be correlated with increased oxidative stress and cellinjury.80,81 The photoprotective effects of topically applied a-tocopherol have been shown to be a reduction in UV-Binduced damage and an inhibition of photocarcinogenesis.82,83 Furthermore, oral and topical vitamin E supplementation have been shown to diminish the effects of photoaging, inhibit the development of skin cancer, and counteract immunosuppression induced by UV radiation in animal models.84,85 In humans, topical application of tocopherol 5–8% cream on the face for 4 weeks has been shown to reduce skin roughness, facial line length, and wrinkle depth when compared with placebo.86 Furthermore, an inhibition of UVinduced expression of human macrophage metalloelastase, a member of the matrix metalloproteinase family involved in the degradation of elastin, has been demonstrated by pretreatment with 5% vitamin E under light-tight occlusion 24 h before UV treatment.87 More recently, however, 400 IU of orally ingested a-tocopherol daily failed to show any meaningful photoprotection in a double-blind, placebo-controlled study.88 Other authors have suggested that, for vitamin E to exert photoprotective effects, it may require interaction with other antioxidants, such as vitamin C.70 This is supported by an animal study showing superior protection against erythema and sunburn cell formation with a combined application of 1% a-tocopherol with 15% L-ascorbic acid compared with either 1%a-tocopherol or 15% L-ascorbic acid alone.89 In addition to its antioxidant activity, topically applied vitamin E is believed to improve wound healing. When taken orally, vitamin E has been demonstrated to lighten facial hyperpigmentation, especiallywhencombinedwithvitaminC.90 As with many botanicals, the incidence of contact dermatitis as a result of topical vitamin E application may be relatively high.91 Topical application of vitamin E has also been linked with contact urticaria, eczematous dermatitis, and erythema multiforme-likereactions.

Green tea

Recently, green tea has gained great popularity in the West; however, it originates in China and has been consumed as a popular beverage in Asia for many years. Its popularity in the Western world can be attributed to its purported antioxidant and anticarcinogenic effects. Of all the antioxidants, green tea is one of the most studied, with numerous in vitro and in vivo investigations examining its effects.92 Green tea, like white tea, is extracted from the Camellia sinensis plant. Special preparation of the tea leaves, with only short steaming and no fermentation, ensures that the antioxidant activities of its ª 2009 The International Society of Dermatology

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polyphenols are preserved. The active ingredients identified in the leaves are flavanols, commonly known as catechins. Green tea consists of four major polyphenolic catechins: (–)epicatechin3-O-gallate (ECG); (–)gallocatechin-3-O-gallate (GCG); (–)epigallocatechin-3-O-gallate (EGCG); and (–)epigallocatechin (EGC). EGCG is the most abundant (30–40% of the dry weight of green tea leaves) and biologically active component, and is mainly responsible for the antioxidant effects.93 The polyphenols contained in green tea have been shown to be potent suppressors of chemical- and UV-induced carcinogenesis when fed orally or applied topically to mice.94,95 In human skin, the photoprotective effects of topically applied green tea polyphenols have been demonstrated by a dose-dependent decrease in UV-induced erythema, a decline in the number of sunburn cells, protection of epidermal Langerhans cells, and decrease in DNA damage.96 The molecular mechanisms involved include Ras and activator protein-1, both of which are a part of the mitogen-activated protein kinase pathway.97 In addition, EGCG has been shown to reduce interleukin-10 production and increase interleukin-12 production, two major cytokines mediating UV-induced immunosuppression, thus reducing UV-induced immunosuppression.98 The EGCG-induced increase in interleukin-12 further leads to augmented synthesis of enzymes repairing UV-induced DNA damage.99 EGCG also seems to reduce collagen degradation, which leads to photodamage by down-regulating the UV-induced expression of activator protein-1 and nuclear factor-jB and suppressing metalloproteinases in mouse skin. In a recent study, green tea polyphenols administered orally pre-exposure were shown to inhibit UV-B-induced protein oxidation and expression of matrix-degrading matrix metalloproteinases in vivo in SKH-1 hairless mice skin exposed to multiple doses of UV-B.100 The same effect was demonstrated in vitro in human skin fibroblast HS68 cells. These data support the role of green tea polyphenols as a potent antiphotoaging compound.

In addition to antioxidant activity, topically applied or orally administered green tea polyphenols possess anticarcinogenic, anti-inflammatory, and depigmentation properties.101,102 That said, studies examining the topical application of green tea-containing products in humans remain limited. Nonetheless, the reported potential of green tea polyphenols to protect the skin from UV-induced damage warrants its topical application in the morning in combination with traditional sunscreens. There are numerous over-the-counter skin care products containing green tea, and green tea is also included in shower gels, toothpastes, depilatories, shampoos, perfumes, and popular soft drinks. When evaluating the utility and efficacy of a skin care product, it is important to determine which form of polyphenol and the percentage concentration in the product. The most effective products contain 50–90% polyphenols. Such high levels of polyphenols render the product brown in color. The patient should therefore be advised that a browncolor isdesirable in thiscase. ª 2009 The International Society of Dermatology

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Pycnogenol

Pycnogenol is extracted from the bark of the French maritime pine tree Pinus pinaster. The extract is rich in condensed flavonoids and monomeric phenolic compounds, such as catechin, epicatechin, taxifolin, and procyanidins, also called proanthocyanidins. Proanthocyanidins are well-known potent free radical scavengers, and the free radical-scavenging effects of pycnogenol have been well documented.103,104 In a recent in vitro study, a correlation between the antioxidant and antimutagenic activities of pycnogenol was shown, which led to the hypothesis that the antimutagenic effects are most probably attributable to its antioxidant properties.105 Oral intake of pycnogenol in humans results in an increased antioxidant capacity of plasma, as measured by the oxygen radical absorbance capacity.106 In addition to its antioxidant activity, pycnogenol possesses anti-inflammatory and anticarcinogenic properties. Topical application of 0.05–0.2% pycnogenol to the irradiated dorsal skin of Skh:hr hairless mice exposed daily to minimally inflammatory solar-simulated UV radiation has been demonstrated to diminish immunosuppression and the inflammatory reaction, as well as to delay tumor formation and reduce tumor prevalence.107 Photoprotection in humans was demonstrated by a significantly increased UV radiation level needed to reachone minimal erythemadose when oralsupplementation with pycnogenol was used. A possible contribution through the inhibition of nuclear factor-jB-dependent gene expression by pycnogenol has also been discussed.108 Finally, pycnogenol can be used as a depigmentation agent. In a 30-day clinical trial, 30 women with melasma supplemented with 25 mg of pycnogenol at each meal, three times a day, showed a significant decrease in the average surface area of melasma.109 Pycnogenol isincludedinsunscreensandvariousotherskincareproducts.

Oatmeal

Wild oats (Avena sativa) have been used for skin care purposes in Egypt and the Arabian Peninsula since 2000 BC. In the 19th and early 20th centuries, oatmeal baths were often used to treat pruritic inflammatory conditions. Subsequent research in the 1950s showed that colloidal oatmeal baths were effective in the management of pediatric atopic dermatitis.110 In the modern dermatologic armamentarium, rolled oats and plain oatmeal have been replaced by colloidal oatmeal, which is composed of dehulled oats ground to a fine powder. Colloidal oatmeal consists mainly of polysaccharides (60%–64%), followed by proteins (10%–18%), lipids (3%–9%), and some remaining constituents, such as enzymes (superoxide dismutase), flavonoids, saponins, vitamins, and inhibitors of prostaglandin synthesis. Colloidal oatmeal is one of the few natural products that the FDA has recognized as an effective skin protectant and, consequently, it is subject to FDA regulation.111 Data suggest that colloidal oatmeal protects and repairs skin and hair damaged from exogenous influences, International Journal of Dermatology 2009, 48, 923–934

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such as UV radiation, free radicals, and smoke, and soothes cutaneous irritation and discomfort. The main use of colloidal oatmeal is as an adjunctive therapy in inflammatory dermatoses and various pruritic skin conditions, such as poison ivy, poison oak, insect bites, chicken pox, and eczema, as it possesses anti-inflammatory activities. Furthermore, colloidal oatmeal has been shown to contribute to the alleviation of pruritus in patients with acute burns.112 Avenanthramides are a newly discovered group of polyphenolic alkaloids, isolated from and found exclusively in oats. Phenolics are known to display a broad range of biologic activities, and oat phenolic compounds, including avenanthramides, have been shown to possess antioxidant effects by scavenging reactive oxygen and nitrogen species, and anti-inflammatory effects by inhibiting prostaglandin biosynthesis.113,114 Other studies support the anti-inflammatory effects of avenanthramides by showing a reduced release of the pro-inflammatory cytokine interleukin-8 by the inclusion of avenanthramides in vitro and an inhibition of nuclear factor-jB, thus inhibiting the activation of inflammatory pathways in the skin. Finally, an amelioration of skin irritation and erythema induced by exposure to UV-B irradiation has also been observed.

Oatmeal is safe, cosmetically stable, and nonirritating. Most oatmeal products come in the form of colloidal baths; however, oatmeal is increasingly found in topical formulations.

Aloesin

Aloesin is derived from Aloe vera and is a C-glycosylated chromone. It acts as a competitive tyrosinase inhibitor, suppressing both the hydroxylation of tyrosine to dihydroxyphenylalanine and oxidation of dihydroxyphenylalanine to dopachinone. In cultured normal melanocytes, aloesin inhibits melanin production.115 Aloesin has been shown to be an even stronger tyrosinase inhibitor than arbutin and kojic acid.116 When administered four times a day for 15 days for hyperpigmentation in human skin after UV radiation, aloesin reduced pigmentation by 34% in a dose-dependent manner; the combination of aloesin and arbutin diminished pigmentation by 63.3% compared with the control.117 Arbutin

Arbutin (C12H16O7), a naturally occurring b-D-glucopyranoside which consists of a molecule of hydroquinone bound to glucose, is traditionally used in Japan, and can be found in the leaves of pear trees and certain herbs, such as wheat and bearberry. It reversibly inhibits melanosomal tyrosinase activity; however, its role as a depigmentation agent is not yet fully understood.118 This is attributable to the fact that, in one study, and increase in pigmentation was observed even though tyrosinase activity was reduced in normal human melanocytes treated with arbutin.119 To the authors’ knowledge, these results have not yet been duplicated, and there are curInternational Journal of Dermatology 2009, 48, 923–934

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rently no published clinical studies evaluating the effects of arbutin on pigmentation disorders. Based on the above data, arbutin is included in skin lighteners, as well as moisturizers, eye creams, and facial cleansers.

Soy

The soybean plant belongs to the pea family (Leguminosae).

Soy can be obtained by eating tofu or soybeans and drinking soymilk. Soy is native to East Asia and has been used for food and medicinal purposes for 5000 years.

It has been shown that soymilk, as well as two proteins derived from soymilk, namely soybean trypsin inhibitor and Bowmann–Birk inhibitor, can induce skin depigmentation by inhibiting protease-activated receptor-2 (PAR-2) activation, a G-protein-coupled receptor responsible for the regulation of the ingestion of melanosomes by keratinocytes.120 The depigmentation effects have been demonstrated in vivo and in vitro and, as the inhibition of melanosome transfer is reversible, sideeffects are rare and the safety profile is excellent. Interestingly, the depigmentation effect has only been observed with fresh soymilk and not with pasteurized soymilk preparations, which suggests that a heat-labile component of soymilk, e.g. soybean trypsin inhibitor, is the active depigmentation agent. In human trials, pigmented spots have been shown to lighten after the application of soybean extract.121 In another large randomized, double-blind, vehicle-controlled study, a novel soy moisturizer containing nondenaturated soybean trypsin inhibitor and Bowmann–Birk inhibitor, administered twice daily for a period of 12 weeks, demonstrated a significant improvement in mottled pigmentation, blotchiness, dullness, fine lines, overall texture, skin tone, and appearance vs. the vehicle.122 In addition to its depigmentation properties, soy contains isoflavones, which have antioxidant and cancer-preventing effects. Soy is included in many skin care products.

Conclusion This discussion of botanical ingredients included or worth including in the dermatologic armamentarium has reviewed some of the currently popular botanicals, their biologic effects, and currently available scientific data. What all discussed botanicals have in common is a need for controlled clinical trials in humans in order to prove what has been shown so far in vitro or in animal models. Furthermore, scientific data obtained on the respective botanical ingredients in vitro and/or in vivo should also be evaluated in the final cosmetic formulation. The scientific validation of the claimed effects on the skin,especially with regard to antiagingclaims, is crucial.

Conflict of interest Dr Leslie Baumann works as an investigator for and is on the advisory board of the following companies: Johnson and ª 2009 The International Society of Dermatology

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Johnson, Philosophy, Revance, Galderma, Loreal, Stiefel, Topix, Mary Kay, Avon, Unilever. Our review paper has not been sponsored by any company.

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