INTRODUCTION

Are certain topically applied metal ions simply innocuous treatments or do they provide real technical benefit? Their use goes back to the earliest recorded medical text (∼1500 BC), the Ebers papyrus of ancient Egypt. For example, calamine (a natural material containing zinc oxide) was described for treating many skin and eye ailments; green copper-based minerals (likely malachite) were used for burn wounds and itching. Many of these applications have withstood the ensuing 3500 years of history, providing a first clue of real technical merit. For example, zinc is still the first choice to soothe a crying baby’s bottom.

This anecdotal support for the importance of metal ions is substantiated by more rigorous investigations, such as those that describe the impact of nutritional deficiencies. A deficiency of zinc can occur either by diet or as a result of a genetic condition that blocks the intestinal uptake, resulting in acrodermatitis enteropathica (AE). AE manifests itself as severe dermatitis in the vicinity of the mouth, nose, ears, and anal areas (orifices), and on the skin and nails of the fingers and toes (acra). Likewise, a disease resulting in copper deficiency, Menkes syndrome, causes defective keratinization in skin and hair growth, manifested by the formation of kinky hair.

While ancient empiricism, practical utility, and clinical manifestations of deficiency support the conclusion that metal ions are important to skin health, a deeper level of understanding is required to confirm this. The molecular basis for these empirical and clinical observations is beginning to emerge that provides strong reinforcement of the links between metal ions and skin condition.

This review will focus specifically on five metals—zinc, copper, selenium, aluminum, and strontium—which are currently used in cosmeceuticals. Each metal will be covered sequentially, reviewing commonly used materials followed by clinical and scientific data supporting their use. There are many other metals that have found usage in cosmeceuticals (see Table 13.1). Searching the skin-related literature (Medline, 1993–present) demonstrates that there is substantial scientific activity exploring the technical basis for utilization of some of these metals. Also summarized in Table 13.1 for some of the metals is the introduction of new personal care products containing them; substantial commercial activity is evident.

ZINC IN COSMECEUTICAL PRODUCTS

• Basis for use of zinc materials

CLINICAL PERSPECTIVE

Damaged skin repairs itself in a very complex process. In the case where the damage is physical and a wound results, a well-defined process ensues: inflammation, re-epithelialization, granulation tissue formation, wound contraction, and tissue remodeling. During wound healing, the requirement for zinc increases dramatically. In rat wound models, local zinc levels are seen to increase after wounding, demonstrating the physiologic need for this metal in the repair process. Topically applied zinc compounds have been shown to speed repair, for example in leg ulcers; the rate of delivery of zinc to the damaged site may be initially rate-limiting in the repair process. The rate of re-epithelialization was increased with topical zinc in a pig model; the nature (bioavailability) of the zinc material was found to be important—sparingly soluble zinc oxide was superior to soluble zinc forms. An indirect measure of local zinc ion activity at a wound repair site comes from monitoring metallothionein (MT), which is responsible for the storage and delivery of zinc to other proteins and enzymes requiring zinc for their function. MT upregulation can be found in vivo by exposure to zinc; treatment of keratinocytes in vitro with a material that selectively binds zinc, inhibits the upregulation of MT and slows cellular proliferation.

Where the damage to skin is more of a ‘chemical’ nature, the dominant manifestation is inflammation. There is a growing body of evidence that zinc has anti-inflammatory activity. Zinc reduces the irritancy caused by surfactants in the oral cavity. This effect has been observed in vitro as well as in skin cultures by monitoring interleukin (IL)-1α production and demonstrating that pyrithione zinc inhibits surfactant-induced IL-1α release. The inflammatory conditions bullous pemphigoid and decubitus ulcers are accompanied (caused?) by low serum zinc levels. The anti-inflammatory benefits of zinc most likely also play a role in the wound-healing process discussed above.

In addition to facilitating repair processes, zinc appears to confer a protective function via providing antioxidant activity. Zinc has been shown to reduce the cellular and genetic damage caused by exposure to ultraviolet (UV) light and enhance resistance of skin fibroblasts to oxidative stress.

Zinc has also recently been shown to improve skin elasticity, reducing the signs of aging skin.

SCIENTIFIC FOUNDATION

An average human contains 2.5 g of zinc and requires 15 mg/day to remain healthy (this is exceeded only by iron for trace elements). The vast majority of the zinc is present in metalloenzymes and proteins. This field was opened in 1940 with the discovery that carbonic anhydrase, a ubiquitous enzyme required for maintaining physiologic pH, was zinc-containing and that the zinc was required for catalytic activity. Since that time, over 300 enzymes requiring zinc for activity have been structurally characterized. Even more impressive are the thousands of zinc-containing proteins that require zinc for conferring a three-dimensional structure that allows them to regulate replication of DNA and transcription of RNA. These proteins form the class called ‘zinc fingers’ and regulate the fundamental biologic process of transcribing genetic information to functional proteins. At least 3% of all proteins encoded for by the human genome have zinc fingers; this has led Berg to coin the phrase ‘galvanization of biology’ to acknowledge the importance of this metal in human physiology.

While it is beyond the scope here to review many of the zinc-containing biomolecules (see Table 13.3 for an overview of important examples), a few will be highlighted that have specific relevance to cutaneous biology and supporting the clinical observations reviewed above. Matrix metalloproteinases (MMPs) are zinc-dependent proteases capable of degrading many molecules important in wound healing, including signaling factors as well as the structural proteins of the extracellular matrix (including collagen and elastin). Wound healing requires intensive cell division and protein synthesis, thus the zinc finger proteins DNA and RNA polymerases are critical throughout this process. The anti-inflammatory role observed clinically for zinc, relevant both in wound healing as well as in other dermatitis conditions, may lie partially in the importance of alkaline phosphatase (AP). AP requires multiple zinc ions and is involved in adenosine monophosphate metabolism, which has a role in restraining an inflammatory response. The breadth of the impacts of these zinc biomolecules on the wound healing process is represented schematically in Figure 13.1.

Table 13.3 Summary of major zinc biomolecules

Fig. 13.1 Overview of the involvement of zinc in the wound-healing process

The observed antioxidant activity of zinc may have its roots in multiple effects:

Zinc is a component of both superoxide dismutase and metallothionein, both of which have strong antioxidant activity.

Zinc may also displace more harmful metal ions (such as copper and iron) which cause oxygen-based free radical formation due to their oxidation–reduction activity.

Zinc does not have this capacity to generate radicals since it does not undergo redox activity.

While this survey barely skims the surface of relevant zinc biochemistry, it should provide substantial confidence that the empirical and clinical observations on the importance of zinc to skin health are indeed real and based on a firm scientific foundation.

COPPER IN COSMECEUTICAL PRODUCTS

SELENIUM IN COSMECEUTICAL PRODUCTS

Selenium is used in relatively few personal care products, as there are only four selenium-containing compounds in the INCI compilation. The most common application utilizes selenium in the form of selenium disulfide as an FDA-accepted antidandruff active. While this material is known to have antifungal activity, it may well exhibit pleiotropic activities associated with antioxidant activity of selenium. Other than the antidandruff application, data to support the human skin activities of topically administered selenium compounds in personal care products are lacking; however, there is an emerging theoretical basis for the idea that selenium-containing compounds could be useful to treat a variety of skin problems ranging from irritation to skin aging and cancer.

An exhaustive review of the biochemistry and pharmacology of selenium is beyond the scope of this chapter, but it should suffice to mention here that selenium is recognized as a trace element that occurs in both organic and inorganic forms, and that the biologic effect of selenium in mammalian cells is an expression of selenium in a wide variety of forms, and not the element per se. Selenium has long been recognized as a dietary antioxidant, and more recently it has been established as an essential component of the active sites of a number of enzymes, including glutathione peroxidase, thioredoxin reductase, and iodothyronine deiodinases. Beyond antioxidant defense, selenium has also been demonstrated to be involved in numerous aspects of mammalian physiology including thyroid hormone homeostasis, immune function, cell cycle control, and apoptosis.

Overall, relatively little is known about how selenium affects skin physiology. The tables below review available published literature related to selenium effects on skin and skin-derived cells. The studies have been separated into work done in mouse skin (Table 13.5) and in human skin/skin-derived cells (Table 13.6). In mouse skin, selenium compounds can protect against UV-induced skin tumors, erythema, pigmentation, DNA damage, and changes in cell-mediated immunity. In human skin/skin-derived cells, selenium compounds have been shown to alter the UVB minimal erythema dose (MED), induce glutathione peroxidase, and decrease UV-induced lipid peroxidation, DNA damage and apoptosis. Some have speculated that all of these effects can be traced to the direct and indirect antioxidant effects of selenium. However, studies in human mammary cells have shown that selenium compounds (e.g. methylselinic acid; MSA) can elicit gene expression profiles that involve alterations in expression of genes involved in cell cycle regulation and apoptosis. In prostate cancer cells, MSA was also shown to modulate the expression of a number of cell cycle regulatory genes, as well as genes involved in inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor-beta signaling. Moreover, work in human lung cancer cell lines has shown that MSA can inhibit cell growth, arrest cell cycle progression at G₁, and induce apoptosis. Interestingly, dietary supplementation with selenized yeast is capable of reducing the overall human cancer morbidity rate by nearly 50%. These and other data prompted the National Cancer Institute to launch the Selenium and Vitamin E Chemoprevention Trial (SELECT) in 2001, a 12-year trial to assess the effect of selenium and vitamin E, individually and in combination, on the incidence of prostate cancer. Thus, there is an emerging appreciation that selenium can influence not only redox status, but also cell cycle control, apoptosis, and differentiation in a variety of epithelia, which has implications for the skin.

While the potential of selenium-based pharmacologic agents for the treatment of skin disease has not been adequately explored, published data from studies in skin and other epithelia provide an intriguing basis for further study. Little is known about the penetration and metabolism of topically administered selenocompounds, or their possible effects on gene expression in the skin. However, if selenium compounds could be adequately delivered to and metabolized by the skin, their pleiotropic effects could prove useful in the treatment of skin conditions that are characterized by altered cell proliferation, differentiation, and inflammation. Synthetic selenocompounds could also be considered as possible topical selenium supplements.

ALUMINUM IN COSMECEUTICAL PRODUCTS

There are several hundred different aluminum compounds listed in the INCI Dictionary; many are colorants or part of the product matrix. Most of the benefit agent materials are associated either with astringents or antiperspirants (some nine different aluminum compounds are accepted by the FDA as antiperspirants).

The vast majority of aluminum salts used topically are used to control perspiration. The process is believed to be primarily physical. Aluminum salts interact with components of the eccrine sweat and precipitate. The precipitate forms at the sweat gland duct, temporarily plugging the orifice and blocking the flow of liquid. These products are available in various physical forms and there is substantial technology in the specific aluminum salt composition and its pharmacology to maximize the efficiency of precipitation and plug formation.

STRONTIUM IN COSMECEUTICAL PRODUCTS

There is even less known about strontium and skin and there are no known strontium-containing proteins. There are eight strontium-containing salts listed in the INCI Dictionary.

The primary use for strontium in personal care products appears to be as an anti-irritant. While the proposed mechanism involves direct interaction between strontium ion and type C nociceptors, the published data do not allow the differentiation of the possibility of chemical interaction between strontium and the potentially irritating species (α-hydroxy acids). More study is needed to firmly establish strontium scientifically.

SUMMARY

The wide use of metal ions in skin care products was initially based primarily on empiricism. From this brief review of the potential scientific data supporting use of the metals, it appears in many cases that there is real basis for understanding why topically applied metals can be beneficial to skin. Of the metals reviewed here—zinc copper, selenium, aluminum, and strontium—varying degrees of scientific pedigree were found in support of their utility. Established and well-based benefits of zinc include both healing damaged skin as well as damage prevention. Copper appears to have similar damage repair benefits, though less well-established scientifically. Selenium’s antioxidant activity is based on specific enzymatic activity; aluminum is well accepted to precipitate with eccrine sweat components to prevent perspiration; strontium’s anti-irritancy activity requires additional scientific support.