What's New in Photoprotection

What’s New in Photoprotection A Review of New Concepts and Controversies

Danielle G. Yeager, MD*, Henry W. Lim, MD

KEYWORDS Photoprotection Photoaging Photocarcinogenesis Sunscreen UV filters Photolyases Antioxidants

KEY POINTS Recent advances, including the discovery of delayed production of cyclobutane pyrimidine dimers and biologic effects of visible light, have resulted in a more thorough understanding of the mechanisms of photodamage. Systemic and topical photoprotective agents, including antioxidants and photolyases, may provide additional protection against both cumulative UV radiation and visible light-induced photodamage. Although data are still evolving, the safety and environmental impact of organic/chemical UV filters has been questioned recently. Dermatologists play a pivotal role in educating patients and the public on photoprotective strategies.

INTRODUCTION nonmelanoma skin cancers and 86% of mela- nomas are related to sun exposure and UVR.2 Cumulative UV radiation (UVR) exposure plays a As a result, photoprotection is one of the most critical role in photoaging, immunosuppression, important preventative health strategies, with photocarcinogenesis and the exacerbation of pho- dermatologists playing a critical role in advising todermatoses. UV-A (320–400 nm) penetrates into patients to implement protective measures. Pho- the dermis and damages DNA by producing reac- 1,2 toprotection includes behavioral modifications, tive oxygen species. It is the major contributor to such as seeking shade when outdoors and wear- photoaging. UV-B (290–320 nm), in contrast, is ing protective clothing, wide-brimmed hats, and responsible for sunburns it directly damages sunglasses. The use of sunscreens and other DNA by the formation of 6-4 cyclobutane pyrimi- products to prevent or counteract the damaging dine dimers (CPDs) and pyrimidine (6–4)pyrimi- 2 effects of UVR are also critical. Despite what is done photoproducts. Both UV-A and UV-B known regarding the danger of cumulative UVR exposure increase the risk of basal cell carcinoma, exposure, adoption of these practices is not squamous cell carcinoma, and melanoma. Ac- undertaken regularly by a large proportion of cording to the Skin Cancer Foundation, 90% of patients. Various obstacles exist, including

Disclosure Statement: D.G. Yeager has no conflicts of interest to disclose. H.W. Lim is an investigator/coinves- tigator for Ferndale, Estee Lauder, Allergan, and Incyte. Dr Lim has served as a speaker at an education sessions organized by Pierre Fabre. Department of Dermatology, Henry Ford Medical Center, 3031 West Grand Boulevard, Suite 800, Detroit, MI 48202, USA * Corresponding author. E-mail address: [email protected]

Dermatol Clin 37 (2019) 149–157 https://doi.org/10.1016/j.det.2018.11.003

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lifestyle preferences and common misconceptions them to convert to their nucleotide monomers in regarding sun protective practices. Sunscreens, preparation for their repair by photolyases.5 which are an integral component in all photopro- Both in vitro and in vivo studies have supported tective regimens, have been questioned recently the beneficial properties of photolyases in prevent- in terms of their safety for users and their environ- ing photodamage.6–8 All human studies were done mental impact. The aim of this article is to provide with sunscreen containing chemical (ie, organic) an overview of new concepts in photoprotection UV filters, with photolyases encapsulated in lipo- and also address current controversies pertaining somes to enhance their penetration through stra- to sunscreens. tum corneum. In another study, the efficacy of sun protection factor (SPF) 50 sunscreen, with or NEW CONCEPTS IN PHOTOPROTECTION without antioxidants (carnosine, arazine, ergothio- Dark Cyclobutane Pyrimidine Dimers nine) and/or photolyases in reducing CPD forma- Formation tion was evaluated. It was found that the combined presence of topical antioxidants and Melanin has traditionally been thought to be pro- photolyases resulted in the greatest reduction in tective against UVR-induced DNA damage and CPDs and free radical-induced protein damage skin cancer development. However, it has been compared with the sunscreen that contained recently found that, in a murine model, melanin either ingredient alone,9 suggesting that antioxi- may also be carcinogenic by contributing to the dants and photolyases might have a synergistic formation of CPDs, even after the completion of effects.9 In patients being treated with photody- UV-A radiation. When melanin is exposed to namic therapy for actinic keratoses, treatment UV-A, it induces superoxide and nitric oxide pro- with sunscreen containing topical photolyases duction, which causes degradation of melanin resulted in longer remission times.10,11 The use and excitation of melanin derivatives into their 3 of photolyase-containing sunscreen in patients high-energy state. It is postulated that these with xeroderma pigmentosum resulted in a lower high-energy melanin derivatives transfer their en- incidence of new actinic keratoses, basal cell car- ergy to DNA, creating mutagenic CPDs hours after cinomas, and squamous cell carcinomas at 1 year UV-A exposure. These CPDs that arise hours after compared with sunscreen alone.12 It should be UV exposure are referred to as delayed or “dark” noted that photolyase-containing sunscreen avail- CPDs. It was further shown that pheomelanin able in the United States at the time of writing has was a more potent generator of dark CPD forma- zinc oxide as the sole UV filter, whereas these tion than eumelanin. Although this study has not studies were done with a product containing been extended to humans, it should be noted chemical filters. that pheomelanin is the predominant melanin in fair skinned individuals, the very skin phototype that is more prone to photocarcinogenesis.3 Role of Visible Light One of the benefits of the delayed formation of Historically, the focus of many photoprotection CPDs for up to 3 hours after UV exposure, should studies was on the effects of UV light. Recently, this occur in humans, is the opportunity for inter- the visible light spectrum, which includes the vention during this time. A goal of future studies wavelengths between 400 and 700 nm, has been may be to develop products to apply after sun found to induce skin pigmentation. UV-B–induced exposure that protect the skin. For example, hyperpigmentation is attributed, in part, to in vitro, the antioxidant vitamin E has been shown increased p53 expression inducing melanogen- to block the formation of light and dark CPDs in esis. Interestingly, when compared with UV-B ra- keratinocytes when added either before or after 4 diation, blue-violet light (part of the visible light UV-A1 exposure. spectrum) has not been found to increase p53 expression.13 The mechanism of visible light- Photolyases in Sunscreens induced pigmentation and melanogenesis is still Photolyases are enzymes that have the property of being actively investigated. repairing CPDs. They are naturally occurring en- A study of 22 patients found that, when exposed zymes in bacteria, plants, and animals that experi- to visible light, patients with skin types IV to VI ence high UV exposure; these enzymes are absent developed darker and more sustained pigmenta- in humans and other placental mammals.5 They tion compared with subjects exposed to repair DNA in the presence of flavonoids, which pure UV-A1. In addition, visible light-induced act as UV chromophores. After absorbing UV pigmentation was observed up to 2 weeks after photons, flavonoids transfer excited electrons to the radiation, a time point when UV-A1–induced the damaged DNA segments (ie, CPDs), causing pigmentation had resolved. These pigmentation

Downloaded for Parkside Library ([email protected]) at University of Wisconsin Madison from ClinicalKey.com by Elsevier on May 30, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved. What’s New in Photoprotection 151 effects were not observed in lighter skin patients of 14 Table 1 skin type II. Histologic specimens in this study Current 17 active sunscreen ingredients found that visible light-induced migration of approved by the US Food and Drug melanin from the basal layer to the upper layers Administration and their range of protection in the epidermis. This finding could explain the sustained effect of pigmentation for up to 2 weeks Active Ingredient/UVa Filter Range of after visible light exposure. Visible light-induced Name Protection pigmentation was irradiance dependent. Further- Organic (chemical) UV filters more, exposure to a light source emitting visible UV-A filters light and a small amount of UV-A1 (0.5%) resulted Avobenzone UV-A1 in more intense pigmentation compared with a exposure to pure visible light.15 Ecamsule (Mexoryl SX) UV-A2 These findings support the concept that visible Meradimate (menthyl UV-A2 light may have a role in conditions aggravated by anthranilate) sun exposure, such as postinflammatory hyper- UV-B filters pigmentation and melasma, especially in darker Aminobenzoic acid UV-B skinned individuals. This finding is of great signif- Cinoxate UV-B icance because the visible spectrum compro- Ensulizole UV-B mises 38.9% of sunlight that reaches the (phenylbenzimidazole surface of the earth.14 Currently available chemi- sulfonic acid) cal (ie, organic) UV filters are not sufficient to pro- Homosalate UV-B tect the skin from the effects of visible light Octocrylene UV-B (Table 1). Similarly, current sunscreens do not Octinoxate (octyl UV-B provide adequate protection for the UV-A1 spec- methoxycinnamate) trum, which acts synergistically with visible Octisalate (octyl UV-B light.15 Although nonmicronized form of zinc ox- salicylate) ide or titanium dioxide would physically block Padimate UV-B visible light transmission, the chalky white appearance of these agents make them aesthet- Trolamine UV-B ically not acceptable to users. Similar to exposure UV-A and UV-B filters to UVR, visible light exposure generates reactive Dioxybenzone UV-A2, UV-B oxygen species; therefore, it is possible that anti- Oxybenzone UV-A2, UV-B oxidants could play a role in decreasing these Sulisobenzone UV-A2, UV-B 16 pigmentary alterations. Inorganic (physical) UV filters Titanium dioxide UV-A2, UV-B Vitamin D and Sunburn Zinc oxide UV-A1, UV-A2, UV-B UV-B is responsible for the conversion of epidermal 7-dehydrocholesterol into active a Approved through New Drug Application process. vitamin D3 (cholecalciferol), which has been found to have various immunomodulatory effects. Prior in vitro and animal studies have proven that proinflammatory mediators of tumor necrosis vitamin D enhances antimicrobial responses, sup- factor-alpha and nitric oxide synthase. This finding presses proinflammatory mediators, and dimin- 17 was attributed to the upregulation of gene expres- ishes inflammation after skin injury. Recently, a sion in the skin of arginase-1, which is antiinflam- pilot study of human subjects displayed that high matory.17 Larger clinical trials are needed to doses of oral vitamin D3 (cholecalciferol) are bene- support the findings of this proof-of-concept ficial in attenuating the sunburn response. Twenty study. patients were randomized to receive either placebo or high doses of oral vitamin D 1 hour after 3 Nontopical Forms of Photoprotection being exposed to 3 minimal erythema doses of simulator solar radiation. compared with the pla- Other nontopical forms of sun protection have also cebo group, subjects who received 200,000 IU of been gaining interest recently to provide additional vitamin D3 had a sustained decrease in skin protection against UVR exposure. Sunscreens redness after the experimental sunburn with with organic and inorganic UV filters do not protect less epidermal damage noted on skin biopsies. against visible light. Systemic photoprotective These subjects also had a decreased release of agents may be beneficial for these reasons.

Several studies have shown that oral and a subcu- darkening. A review of both human and basic sci- taneously administered agent have been shown to ence studies found no significant adverse effects be effective in reducing photodamage, but larger of oral P leucotomos extract.23 studies are still needed to confirm their efficacy Nicotinamide is the active amide form of vitamin (Table 2). B3 (niacin; nicotinic acid) and is a cofactor for Polypodium leucotomos extract is derived from adenosine triphosphate, which is essential in a fern plant that is native in Central and South DNA repair in the skin.24 It is safe and widely avail- America. It has been shown to have antioxidative able over the counter. Unlike niacin, it does not and antiinflammatory properties. As an antioxi- cause a flushing reaction. UVR typically inhibits dant, P leucotomos extract decreases lipid per- adenosine triphosphate production and prevents oxides and neutralizes superoxide anions and optimal skin immune response and DNA repair. hydroxyl radicals after UV exposure.18 Its antiin- This pathway is ultimately responsible for photo- flammatory properties are attributed to reduced carcinogenesis. In human keratinocytes, nicotin- UV-induced cyclooxygenase-2 expression, amide blocks the inhibitory effect of UV on p53 suppressor gene mutations, and formation adenosine triphosphate production, enhances of CPDs and inflammatory infiltrate in animal DNA repair, and decreases the formation of models.18 CPDs.24 In a phase II clinical trial, subjects with Human studies have shown that P leucotomos sun-damaged skin who took 500 mg once or twice extract increases the UV dose required for imme- daily had 29% and 35%, respectively, fewer diate pigment darkening, minimal erythema dose, actinic keratoses at 4 months.25 A phase III trial and minimal phototoxic dose.19,20 It is protective demonstrated that nicotinamide might be benefi- against UV-B and psoralen plus UV-A–induced cial as chemoprevention in subjects with a history phototoxicity.21 It has also been found to be bene- of 2 or more nonmelanoma skin cancers. Subjects ficial in preventing polymorphous light eruption, who received nicotinamide 500 mg twice daily had solar urticarial, and other photodermatoses.22 23% lower rates of new nonmelanoma skin can- Current studies are being performed to assess cers and 11% fewer actinic keratosis compared its efficacy in protecting against visible light- with placebo at 12 months.26 Notably, consistent induced delayed tanning and persistent pigment with the proposed mechanism of action of

Table 2 Nontopical forms of photoprotection

Product Source Mechanism Clinical Uses Polypodium Tropical fern Neutralization of superoxide Reducing immediate pigment leucotomos anions, lipid peroxides and darkening extract hydroxyl radicals Increasing minimal erythemal Reduced cyclooxygenase-2 dose and minimal expression, p53 suppressor phototoxic dose gene mutations, Preventing polymorphous cyclobutane pyrimidine light eruption and other dimers, sunburn cells, and photodermatoses inflammatory infiltrate Nicotinamide Active form of Prevent UVR-induced Chemoprevention of actinic vitamin B3 intracellular depletion of keratosis and nonmelanoma (niacin) adenosine triphosphate skin cancers Boosts cellular energy and enhances DNA repair Afamelanotide Analogue of Stimulates eumelanin Photoprotective in patients alpha-melanocyte- production in the epidermis with erythropoietic stimulating without UV-induced cellular protoporphyria hormone damage Possible role in polymorphous Results in eumelanin that light eruption, actinic absorbs UV light, reduces keratosis in organ free radicals and reactive transplant patients and oxygen species solar urticaria

Abbreviations: UVR, UV radiation.

Downloaded for Parkside Library ([email protected]) at University of Wisconsin Madison from ClinicalKey.com by Elsevier on May 30, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved. What’s New in Photoprotection 153 preventing UV-induced suppression of adenosine Notice that the photons transmitted are halved triphosphate production, this response is not sus- despite the seemingly small difference in the tained once nicotinamide is discontinued. percent of EIR absorbed (Table 3). Afamelanotide is a structural analogue of alpha- A recent survey found that, when sunscreen melanocyte–stimulating hormone and acts as an SPF is presented as percent of EIR absorbed agonist of melanocortin-1 receptor. It promotes compared with percent transmitted, dermatolo- the synthesis of melanin (eumelanin) without the gists underestimated the increased protection UV-induced cellular damage that occurs with UV provided by the higher SPF sunscreen.33 It is pho- exposure.27 It has been found to be photoprotec- tobiologically and clinically more relevant to tive in patients with erythropoietic protoporphyria assess the amount of UV photons transmitted, and solar urticaria by stimulating melanogenesis especially in the setting of chronic sun exposure. and acting as an antioxidant.28,29 In phase II and Higher SPF sunscreens are more beneficial for phase III trials in Europe and the United States, long-term cumulative photoprotection. patients with erythropoietic protoporphyria were administered 16 mg subcutaneously every Safety of Oxybenzone and Other Sunscreen 60 days; they had an improved quality of life and Active Ingredients longer pain-free periods after sun exposure.30 In combination with narrowband UV-B phototherapy, Oxybenzone (benzophenone-3) is a widely used it has also been demonstrated to accelerate repig- broad-spectrum organic filter that is protective mentation in vitiligo.27 against UV-B and UV-A2 (see Table 1).34 In a 2018 report, it was estimated to be in two-thirds of nonmineral sunscreens in the United States.34 CONTROVERSIES ON SUNSCREENS However, concerns have been raised about UV Blocked Versus Transmitted its photoallergic potential, systemic absorption, SPF is a well-known term used to communicate endocrine side effects, and environmental how effective a sunscreen is in protecting against impact.35 erythema-induced radiation (EIR). An incorrect In 2014, benzophenones were named the Amer- misconception made by many is generalizing ican Contact Dermatitis Society’s Contact that SPFs beyond 30 provides only minimal addi- Allergen of the Year. Of all the UV filters, it is the tional protection.31,32 This misconception might most common cause of photoallergy and contact stem from the way that SPF is commonly pre- allergy reactions.36 In a large 10-year retrospective sented as percent of EIR absorbed and not study, a review of the patients who listed an allergy percent of EIR transmitted. This approach is to sunscreen found that 70.2% had a positive misleading because only photons that are trans- patch test reaction to oxybenzone.36 In the Euro- mitted are absorbed and have biologic effects. pean Union, oxybenzone has been largely For example, when comparing percent absorbed replaced with other broad-spectrum UV filters. Un- of SPF 30 with SPF 60, it is 96.7% EIR absorbed fortunately, this replacement cannot be easily compared with 98.3% EIR absorbed. However, if done in the United States because many of those comparing the number of photons transmitted filters are not yet approved by the US Food and when exposed to 60 photons, SPF 30 allows 2 Drug Administration to be used in the United photons to be transmitted, and SPF 60, 1 photon. States.

Table 3 Comparison of 2 different ways to display SPF protection: percent transmitted versus percent absorbed

% EIR Transmitted % EIR Absorbed SPF 1 100% transmitted Â 60 photons 5 60 photons 0% absorbed Â 60 photons 5 0 photons transmitted absorbed SPF 15 6.7% transmitted Â 60 photons 5 4.02 93.3% absorbed Â 60 photons 5 55.98 photons transmitted photons absorbed SPF 30 3.3% transmitted Â 60 photons 5 1.98 96.7% absorbed Â 60 photons 5 58.02 photons transmitted photons absorbed SPF 60 1.7% transmitted Â 60 photons 5 1.02 98.3% absorbed Â 60 photons 5 58.98 photons transmitted photons absorbed

Abbreviations: EIR, erythema-induced radiation; SPF, sun protection factor. Studies have found that when SPF data are presented as %EIR absorbed, their protective effects are underestimated.

In addition, oxybenzone has been found to have that although oxybenzone has been in used in endocrinologic effects in fish and rats.37–39 In fish it the United States since 1978, no adverse systemic has been shown to have antiandrogenic and anti- effects have been reported in humans. estrogenic effects. Chronic exposure to oxyben- There are also concerns regarding the potential zone in fish resulted in decreased egg production for many UV filters to damaging marine environ- and egg hatchings. In rats, a dose-dependent es- ments; these filters include oxybenzone, octocry- trogenic effect was observed when these animals lene, octinoxate, and ethyl hexyl salicyclate.35 were given high doses of oxybenzone (1500 mg/ In vitro, oxybenzone has shown to cause bleach- kg/d) in their drinking water.39 In humans, it has ing of coral reefs, inducing ossification and been estimated that, if one applies sunscreen at deforming DNA in the larval stage.42 A study 2 mg/cm2, which is the dose used for SPF testing, measuring the concentrations of oxybenzone in to 100% of their body surface, it would take almost seawater in various locations, including Hawaii 35 years of daily application to achieve the serum and the US Virgin Islands, found varying detect- levels detected in rats used in that study.40 Short- able levels from 0.8 mg/L to 1.4 mg/L. This study term studies that evaluated topical application of also reported that the coral cell median lethal con- UV filters including oxybenzone in humans found centration of oxybenzone for 7 different coral spe- that there were no significant UV filter-related al- cies ranges from 8 to 340 mg/L over 4 hours of terations in endocrinologic, reproductive, or thy- exposure.42 These concerns have led to Hawaii roid function.40,41 It should also be emphasized to pass a legislative bill that prohibits the sale

Table 4 Additional topical antioxidant agents

Antioxidant Function and Use Soy (Glycine soja) extract Genistein phytoestrogen compound in soy causes dose-dependent UV-induced DNA damage and pyrimidine dimer formation.48 Vitamin C (L-ascorbic acid) Topical concentrations of at least 10% are photoprotective, reducing erythema and immunosuppression. Protects from UV-B and UV-A– induced erythema and sunburn cell formation.49 Vitamin E (tocopherols Protects against UV-induced lipid peroxidation, UV- induced photoaging, and tocotrienols) immunosuppression and photocarcinogenesis. Inhibits UV-induced CPD formation and inhibits melanogenesis.49 Grape seed extract (Vitis Inhibition of UV-mediated edema and inflammation. Inhibits vinifera) inflammatory mediation cyclooxygenase-2, reduces hydrogen peroxide and causes decrease lipid peroxidation. Rapid metabolism makes it challenging for topical use unless encapsulated in lipid nanoparticles.50 Tea polyphenols Epigallocatechin-3-gallate inhibits UV-B–induced release of hydrogen peroxide, and prevents phosphorylation of mitogen-activated protein kinase.51 Reduces inflammation through nuclear factor kappa B pathway. Dose dependent inhibitor of UVR-induced erythema.51 Selenium Protects against UV-induced DNA oxidation, IL-10 expression and lipid peroxidation. Protects against UV-induced erythema and skin cancer in mice. In humans, caused a dose-dependent increase in minimal erythema dose.49 Melatonin Protects against UV-induced erythema, decreased production of reactive oxygen species, enhanced p53 expression, improved DNA repair and decreased CPD generation.49 Algae extract Stimulates proteasome peptidase activity in irradiated human keratinocytes, reducing the extent of protein oxidative damage.52 Silymarin milk thistle Enhances repair of UV-B–induced DNA damage through the nucleotide (Silybum marianum) excision repair pathway. Accelerates DNA repair in human dermal fibroblasts after UV-B irradiation through a p53-dependent repair pathway.53 Aloe vera leaf extracts Reduces UV-A–induced redox imbalance, decrease UV-A–associated lipid membrane oxidation and increase overall cell survival.54

Abbreviations: CPD, cyclobutane pyrimidine dimers; UVR, UV radiation.

Downloaded for Parkside Library ([email protected]) at University of Wisconsin Madison from ClinicalKey.com by Elsevier on May 30, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved. What’s New in Photoprotection 155 and distribution of oxybenzone and octinoxate. door for additional therapeutic options, including The bill was signed into law by the governor on systemic photoprotective agents and additional July 3, 2018, and will take effect in January 2021. topical agents including antioxidants and photolyases. Proper education of the public should Nanoparticle Free Radical Damage to the Skin continue to be done on photoprotection, which includes seeking shade when outdoors, wearing The safety of broad-spectrum inorganic UV filters photoprotective clothing, wide brimmed hats and or physical sunscreens, titanium dioxide, and zinc sunglasses and applying broad spectrum, with oxide has also been questioned. Titanium oxide an SPF 30 or greater sunscreen. Although data and zinc oxide are formulated as nanosized prod- are still evolving, for those who are concerned ucts that blend more easily into the skin. When about the environmental impact of organic/chem- exposed to UV light in vitro, titanium oxide and ical UV filters, sunscreens with inorganic/physical zinc oxide emit electrons and generate free radi- filters can be used. cals and reactive oxygen species.43 The major concern is that, when exposed to UVR, these nanoparticles may have the potential to damage REFERENCES proteins, lipids, and DNA. It should be noted 1. Wang SQ, Balagula Y, Osterwalder U. Photoprotec- that all nanoparticles used in sunscreens are tion: a review of the current and future technologies. coated (usually with silica), greatly limiting the Dermatol Ther 2010;23:31–47. amount of free radicals that are released into the 2. Cohen LE, Grant RT. Sun protection: current man- microenvironment. 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