Arbutin attenuates CFA-induced arthritis by modulating expression levels of 5-LOX, NF­κB, IL-17, PGE-2 and TNF-α.

Arbutin, a naturally soluble glycosylated phenol has antioxidant, antimicrobial, antitumor and anti-inflammatory properties. The current exploration appraises the treatment of arthritis by use of Arbutin (25, 50 and 100 mg/kg) orally in CFA-induced rat arthritis model. Body weight changes, paw size, and joint diameter were recorded till the 28th day in the arthritic-induced rats. Hematological, biochemical, oxidative and inflammatory biomarkers were measured through the blood samples of anesthetized rats. Arbutin markedly decreased paw volume, PGE-2, anti-CCP and 5-LOX levels, however, maintained metabolic and hematological balance and prevented weight loss. Radiology and histology changes improved significantly in the ankle joints of rats. Moreover, Arbutin increased gene pointers such as IL-10 and IL-4 while significantly reducing the levels of CRP and WBCs, whereas Hb, platelets and RBCs count markedly raised in post-treatments. Antioxidant levels of SOD, CAT and GSH were improved and MDA level was reduced in treated groups. Rt-PCR investigation showed a significant reduction of the interleukin-1ß, TNF-α, interleukin-6, cyclooxygenase-2, NF-κB and IL-17 and increased expression of gene pointers like IL-4, and IL-10 in treated groups. Assessment of molecular docking revealed a strong binding interaction of Arbutin against 5-LOX, IL-17, TNF-alpha and interleukin-6, cyclooxygenase-2, nuclear factor-κB, IL-4 and iNOS providing a strong association between experimental and theoretical results. As a result, Arbutin has significantly reduced CFA-induced arthritis by modulation of anti-inflammatory cytokines, i.e., IL-10 and IL-4, the pro-inflammatory cytokines panel such as NF-κB, TNF-alpha, IL-1ß, IL-6, PGE-2, 5-LOX and COX-2 and oxidative biomarkers.

Arbutin intervention ameliorates memory impairment in a rat model of lysolecethin induced demyelination: Neuroprotective and anti-inflammatory effects.

Cognitive impairment (CI) and memory deficit are prevalent manifestations of multiple sclerosis (MS). This study explores the therapeutic potential of arbutin on memory deficits using a rat hippocampal demyelination model induced by lysophosphatidylcholine (LPC). Demyelination was induced by bilateral injection of 1% LPC into the CA1 area of the hippocampus, and the treated group received daily arbutin injections (50 mg/kg, i.p) for two weeks. Arbutin significantly improved memory impairment 14 days post-demyelination as assessed by Morris water maze test. Histological and immunohistochemical analyses demonstrated that arbutin reduced demyelination suppressed pro-inflammatory markers (IL-1ß, TNF-α) and increased anti-inflammatory cytokine IL-10. Arbutin also diminished astrocyte activation, decreased iNOS, enhanced anti-oxidative factors (Nrf2, HO-1), and exhibited neuroprotective effects by elevating myelin markers (MBP) and brain derived neurotrophic factor (BDNF). These findings propose arbutin as a potential therapeutic candidate for multiple sclerosis-associated memory deficits, warranting further clinical exploration.

The whitening efficacy of a compound formula examined using an ultraviolet-induced skin melanization model.

BACKGROUND: In Eastern culture, a fair complexion is the standard of beauty, leading to appearance-related distress among women with darker skin or facial pigmentation. Women seek whitening cosmetics to enhance their skin tone or correct their pigmentation, but their safety and effectiveness are paramount factors to consider. In this study, we evaluated the safety and whitening effects of a compound formula denoted as TEST comprising astaxanthin, nicotinamide, arbutin, and tranexamic acid. METHODS: Primary skin irritation and skin-whitening efficacy were examined. Three qualified melanization areas were treated with TEST, 7% ascorbic acid, or a blank. Skin color, the individual type angle (ITA°), and the melanin index (MI) were compared among treatment areas. RESULTS: TEST did not induce a skin response and exhibited a significantly higher ITA° than the blank, while no significant difference was observed with that of 7% ascorbic acid. Furthermore, the MI of TEST was significantly reduced posttreatment. CONCLUSIONS: TEST could be integrated into spot-fading and skin-whitening cosmeceuticals or functional cosmetics.

Arbutin ameliorated ulcerative colitis of mice induced by dextran sodium sulfate (DSS).

Accumulating evidence has revealed the anti-inflammatory effects of arbutin against various diseases. However, the effects of arbutin are not clarified in ulcerative colitis. This study was intended to investigate the protective effects and mechanisms of arbutin on DSS-induced colitis. Hematoxylin eosin staining was performed to determine the pathological damage of intestinal tissue in mice. Inflammatory factors levels in intestinal tissue were detected by enzyme linked immunosorbent assay (ELISA) assay. TUNEL staining showed the apoptosis levels of cells. Intestinal permeability was analyzed using the application of Fluorescein isothiocyanate Dextran (FD) 4. The levels of Zona Occludens 1 (ZO-1), occluding and claudin-1, and the related proteins in MAPK/ELK1 pathway were analyzed by Western blot. DSS promotes pathological injury, the levels of pro-inflammatory factors containing tumor necrosis factor alpha (TNF-α), Interleukin- 6 (IL-6) and myeloperoxidase (MPO), and cell apoptosis in the mouse colon. Additionally, intestinal permeability was increased and the levels of tight function-related proteins were increased following DSS induction. Its effects could be greatly improved by arbutin. Arbutin exerted effects by eliciting anti-inflammatory effects and maintaining normal intestinal mucosal barrier function, the action mechanism of which could be associated with MAPK/ELK1 pathway.

Arbutin attenuates ethanol-induced acute hepatic injury by the modulation of oxidative stress and Nrf-2/HO-1 signaling pathway.

Alcoholic liver disease (ALD) is a pervasive ailment due to the excessive consumption of alcohol and there is no operative drug for its treatment. The current exploration was intended to examine the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats via the modulation of the Nrf-2/HO-1 signaling cascade. Wistar rats were challenged with the 3 g/kg/day (40% v/v) of ethanol for 4 weeks to provoke the ALD and concomitantly supplemented with 40 mg/kg of arbutin. The liver function markers enzymes, inflammatory cytokines, and oxidative stress markers levels were scrutinized by using the respective assay kits. The mRNA expression of Nrf-2/HO-1 signaling proteins was studied by reverse-transcription polymerase chain reaction. The histological alterations of liver tissues were examined. HepG2 cells were used for the in vitro studies. The levels of oxidative stress markers and liver marker enzymes were examined by using kits. Reactive oxygen species (ROS) and apoptotic cell death was detected by using fluorescent staining. There were no major differences in the body weight and liver weight of experimental animals. Arbutin treatment appreciably reduced the liver marker enzymes, upregulated superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and the hydroxyl scavenging ability, and diminished the tumor necrosis factor-α and interleukin-6 levels in the serum of ethanol provoked animals. Arbutin triggered Nrf-2/HO-1 signaling cascade liver tissues of ethanol-provoked animals. Histological findings proved the preventing effects of arbutin. Arbutin did not demonstrate toxicity to the HepG2 cells. It reduced the aspartate aminotransferase and alanine aminotransferase, ROS, apoptotic cell death, lipid peroxidation and improved the antioxidants' levels in the ethanol-challenged HepG2 cells. In conclusion, our findings unveiled the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats. It could be a promising agent to treat alcoholic liver disease in the future.

Fabrication, characterization and comparison of α-arbutin loaded dissolving and hydrogel forming microneedles.

In this study, polyacrylic acid-co-maleic acid (PAMA) and polyvinyl alcohol (PVA) (1:4) were used to fabricate dissolving microneedles (DMNs) and hydrogel forming microneedles (HMNs) which incorporated α-arbutin. Αlpha-arbutin is commonly used as a skin lightening agent. However, it has poor penetration ability due to its hydrophilic properties. The purpose of this study was to compare the permeation of α-arbutin into the skin using DMNs and HMNs. Both types of microneedles (MNs) were sharp, strong with elegant appearance and approximately 100% penetrated the neonatal porcine skin. All needles of α-arbutin loaded DMNs were completely dissolved within 45 min, whereas maximum swelling of HMNs was observed at 4 h. In vitro permeation studies showed that α-arbutin loaded DMNs and HMNs provided significantly about 4.5 and 2.8 times, respectively, greater α-arbutin permeability than gel and commercial cream (P < 0.05). In vivo study also showed high intradermal delivery of α-arbutin levels using DMNs (5.33 µg/mL) and HMNs (1.47 µg/mL) when compared to that of commercial cream 0.15 µg/mL. Moreover, the micro-holes caused by applying MNs can reseal within 1 h. MNs were also stable at 25 °C for 3 months. The results suggested that DMNs and HMNs developed have a promising platform for transdermal delivery.

HPMC/PVP Dissolving Microneedles: a Promising Delivery Platform to Promote Trans-Epidermal Delivery of Alpha-Arbutin for Skin Lightening.

Alpha-arbutin is one of the most efficient skin lightener agents, which shows the effect on reducing the pigmentation by competitively inhibiting human tyrosinase. However, alpha-arbutin has difficulty in skin permeability due to its hydrophilic property. The objective of this study was, therefore, to develop alpha-arbutin-loaded dissolving microneedles (DMNs) for improving the delivery of alpha-arbutin into the skin. The DMN patch was prepared using Gantrez™ S-97, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone K-90 (PVP), chitosan, and their combinations. The optimal 8% alpha-arbutin-loaded DMNs, aside from Gantrez™ S-97, was successfully formulated with combination of 8% w/w HPMC and 40% w/w PVP K-90 (HPMC/PVP) at the weight ratio of 1:1. Both DMNs had 100% of penetration into porcine skin. Over 12 h of skin permeation, the flux of Gantrez™ S-97 DMNs and the HPMC/PVP DMNs were 66.21 µg/cm2/h and 74.24 µg/cm2/h, respectively. The accumulation amount of alpha-arbutin in the skin from Gantrez™ S-97 DMNs and HPMC/PVP DMNs was 107.76 µg and 312.23 µg, respectively. In comparison to the gel formulations, Gantrez™ S-97 DMNs and HPMC/PVP DMNs increase the delivery of alpha-arbutin across the skin approximately 2 and 4.7 times, respectively. In vivo studies found that alpha-arbutin-loaded HPMC/PVP DMNs delivered more alpha-arbutin into the skin than commercial cream. Moreover, the skin can reseal naturally after removal of DMNs patch without any signs of infection and remain stable in accelerated conditions for 4 weeks. Accordingly, alpha-arbutin-loaded HPMC/PVP DMNs could be a promising delivery platform for promoting trans-epidermal delivery of alpha-arbutin for skin lightening.

Randomized control trial outcomes of tranexamic acid combination serum as a depigmenting agent for the use in healthy individuals.

To compare the effectiveness of tranexamic acid (TA) combination serum with hydroquinone, the gold standard in whitening agents for healthy populations. This was a three-arm randomized controlled trial. The subjects were divided into three groups: the first group received 3% TA combination serum (3% TA, 4% galactomyces ferment filtrate, 2% niacinamide, and 4% alpha arbutin), the second group received 2% TA combination serum, and the third group received 4% hydroquinone. One milliliter of each serum was applied on three holes: Hole A, which was located 4 cm from the left cubital fossa, Hole B, which was located 4 cm from the first hole, and Hole C, which was located 4 cm from the right cubital fossa. The skin brightness and pigmentation intensity were evaluated each week for 4 weeks using a chromameter. A total of 44 subjects were recruited for this study. All groups showed a significant improvement in skin brightness and pigmentation intensity after 4 weeks (p < .001). There were no differences between the treatment groups and hydroquinone (p > .05). TA serum (2 and 3%) combined with 4% galactomyces ferment filtrate, niacinamide, and alpha arbutin is an effective depigmenting agent.

Synthesis of arbutin-gold nanoparticle complexes and their enhanced performance for whitening.

Arbutin, a natural polyphenol, possesses numerous biological activities including whitening, anti-oxidant, anti-cancer, anti-inflammatory activities, as well as strong reducing power, making it an ideal bioactive ingredient for preparing gold nanoparticles (GNPs). Previously, we developed a novel green, mild synthetic method for GNPs using glycosides such as arbutin as reducing agents and stabilizers. Herein, we optimized the synthetic method for glycoside-GNPs using arbutin, methyl ß-D-glucoside, and phenyl ß-D-glucoside and validated their whitening efficacy in vitro and in vivo. The resulting glycoside-GNPs were predominantly mono-dispersed and spherical (10.30-17.13 nm diameter). Compared with arbutin itself, arbutin-GNP complexes (GNP-A1 and GNP-P2) displayed enhanced whitening capabilities. Furthermore, GNP-P2 exhibited enhanced anti-inflammatory activity and lacked the toxicity associated with arbutin. Bioactive glycoside-GNP complexes may open new directions for cosmeceuticals, and GNP-P2 may serve as a useful whitening ingredient in future cosmeceutical applications.

Impact of phenolic compounds on Meloidogyne incognita in vitro and in tomato plants.

Exposing second-stage juveniles (J2) of Meloidogyne incognita in vitro to a phenolic compound sometimes fails to cause J2 mortality, but in tests in vivo the same compound may reduce the infectivity and population of the nematode. This work aimed to study the effect of phenolic compounds on M. incognita through in vitro and in vivo assays. In the in vitro assay 49 phenolic compounds were screened for their toxicity to M. incognita J2. As a result, D-(-)-4-hydroxyphenylglycine, t-butylhydroquinone, L-3-(3,4-dihydroxyphenyl)alanine, sesamol, 2,4-dihydroxyacetophenone, and p-anisaldehyde increased the J2 mortality. These compounds presented, respectively, the following lethal concentrations to 50% of J2 (LC50): 365, 352, 251, 218, 210, and 85 µg/mL, while Carbofuran (positive control) had 150 µg/mL. However, none of these compounds were efficient in controlling the nematode in inoculated tomato plants, even when 2.77-fold of their LC50 were used. Although inactive in the in vitro test at 500 µg/mL, hydroquinone (3.5 mg per plant) reduced M. incognita population and galls by up to 99% to levels similar to the nematicide Carbofuran (1.2 mg per plant). Additionally, hydroquinone increased the root weight when compared to the negative and positive controls, water/NaOH and Carbofuran, respectively. In this study, we showed that some phenolic compounds, hydroquinone in particular, revealed a potential new option for the control of M. incognita.

Effectiveness and safety of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment in the management of patients with post-trauma/surgery persistent hand edema: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness and safety of oral administration of Linfadren® in addition to conventional treatment in patients with post-trauma/surgery persistent hand edema. DESIGN: Parallel-group randomized controlled trial. SETTING: Outpatient rehabilitation center. SUBJECTS: A total of 60 outpatients (mean age 48.5 (standard deviation (SD) = 12.3) years) with post-trauma/surgery persistent hand edema. INTERVENTIONS: Patients were randomized to either receive six-week conventional treatment plus Linfadren® (Study Group) or conventional treatment (Control Group). MAIN MEASURES: Primary outcome was hand edema as measured by figure-of-eight method. Secondary outcomes were hand function, patient's overall perceived treatment effectiveness and rescue medication request. Tolerability of Linfadren® was also evaluated. Assessments were performed at baseline, at the end of treatment and three months after the end of treatment. RESULTS: All patients completed the six-week program and 57 patients (95%) completed the three-month follow-up. At six weeks, the Study Group had significantly greater improvement in hand edema (423.3 (SD = 23.8) mm vs 439.4 (SD = 22.6) mm; P = 0.009) and upper limb function ( Quick Disabilities of Arm, Shoulder and Hand questionnaire: 23.6 (SD = 13.6) vs 37.7 (SD = 15.9); P = 0.005) compared to the Control Group. Moreover, the percentage of patients who perceived treatment as effective was significantly higher in the Study Group than in the Control Group both after treatment (70% vs 37%, P = 0.002) and at follow-up (77% vs 30%, P < 0.0001). The rescue medication request was not different between groups. No adverse events were recorded. CONCLUSION: Linfadren® in addition to conventional treatment was safe and more effective than conventional treatment alone in patients with post-trauma/surgery persistent hand edema.

Effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy on management of breast cancer-related lymphedema.

PURPOSE: To assess the effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy (CDT) on the management of patients with a breast cancer-related lymphedema (BCRL). METHODS: Fifty outpatients (average age of 56.2 ± 2.7 years, range 28-71) with a BCRL were enrolled for this study. Patients were randomly assigned (1:1 ratio) to receive either CDT consisting of skin care, manual lymphatic drainage, remedial exercises, and elastic compression garment (control group, n = 25) or CDT plus Linfadren® (study group, n = 25). Patients were evaluated before and after treatment and 3 months after the end of treatment. Primary outcomes were reduction of upper limb excess volume (EV) and percentage reduction of excess volume (%REV). Secondary outcomes were improvement in Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire, and patient's perception of treatment effectiveness (PPTE). RESULTS: Addition of Linfadren® to CDT yielded an additional reduction of primary outcomes both after treatment (EV, - 521 ml vs. - 256 ml, P < 0.0001; %REV, - 66.4% vs. - 34%, P = 0.02) and at 3-month follow-up (EV, - 59 ml vs. + 24 ml, P < 0.0001; %REV, - 73.6% vs. - 31.4%, P = 0.004). Moreover, statistically significant differences were found between the two groups for the secondary outcomes after treatment (QuickDASH, P = 0.006; PPTE, P = 0.03) and at 3-month follow-up (QuickDASH, P = 0.006; PPTE, P = 0.02). No patient showed adverse events. CONCLUSIONS: Linfadren® in addition to CDT was a safe and effective therapy for reducing BCRL and was better than CDT alone.

Investigation of the pro-apoptotic effects of arbutin and its acetylated derivative on murine melanoma cells.

Arbutin, a natural polyphenol isolated from the bearberry plant Arctostaphylos uvaursi, possesses whitening and anticancer properties. The effects of arbutin on melanogenesis and its pro-apoptotic effect on B16 murine melanoma cells have not yet been reported. In the present study, acetylated arbutin was prepared in order to improve the biological effects of arbutin, and it was found to significantly inhibit the biosynthesis of melanin and tyrosinase activity compared with parent arbutin in B16 murine melanoma cells. Interestingly, only acetylated arbutin strongly inhibited B16 murine melanoma cell migration in a dose-dependent manner. Both arbutin and acetylated arbutin significantly reduced cell viability, promoted cell apoptosis, caused G1 cell cycle arrest and induced mitochondrial disruption in B16 murine melanoma cells. Furthermore, reduced expression of B-cell lymphoma­extra large (Bcl-xL) and Bcl-2 were observed in arbutin- and acetylated arbutin-treated cells. Therefore, arbutin and acetylated arbutin were found to exert pro-apoptotic effects on B16 murine melanoma cells, mediated through the mitochondrial pathway. The findings of the present study also support the use of acetylated arbutin as a new potential candidate agent for skin whitening and melanoma treatment.

Arbutin encapsulated micelles improved transdermal delivery and suppression of cellular melanin production.

BACKGROUND: Hyperpigmentation is a skin disorder characterized by elevated production of melanin. Current treatment approaches mainly rely on the application of skin lightening chemicals, most of which have safety issues. Efficacy of delivery of the active ingredients to the target organ has also been a challenge. Transdermal based drug delivery platform has been shown to improve drug bioavailability, avoiding the hepatic first pass metabolism, decrease gastrointestinal side effects, and eventually enhance patient compliance. RESULTS: This article explores the utilization of micellar transdermal delivery technology to improve skin penetration and efficacy of arbutin, a hyperpigmentation agent. The suppression efficacy of cellular melanin production versus cell viability of four active ingredients commonly used in skin lightening products, namely allantoin, arbutin, glycolic acid, and hyaluronic acid were first compared. Arbutin was selected for the micellar delivery studies base on its comparatively low cytotoxicity and better performance in reducing melanin production. Micellar Arbutin cream was formulated using Urah® proprietary micellar technology and was assessed for its cellular melanin suppression efficacy and skin penetration capacity. CONCLUSION: The results show that micellar arbutin cream improved both the delivery and cellular melanin suppression, suggesting that micellar transdermal delivery may have potential application in addressing hyperpigmentation skin disorders. Graphical abstract Transdermal delivery of arbutin with micelles for melanin production suppression.

Penetration depth, concentration and efficiency of transdermal α-arbutin delivery after ultrasound treatment with albumin-shelled microbubbles in mice.

Recently, the feasibility and effects of using microbubbles (MBs) as an ultrasound (US) contrast agent for enhancing the penetration in transdermal delivery in vivo have been demonstrated, but the mechanism and efficiency are unclear. This study demonstrates the penetration depth, concentration and efficiency of transdermal α-arbutin delivery during 4 weeks after US treatment with MBs in mice. Experimental animals were randomly divided into the following four groups (n = 5 animals per group): (1) penetrating α-arbutin alone (C), (2) US combined with penetrating α-arbutin, (3) US combined with MBs and penetrating α-arbutin, and (4) US combined with diluted MBs and penetrating α-arbutin (UBD). The penetration depths in agarose phantoms and pigskin were 47 and 84% greater for group UBD, respectively, than for group C. The in vitro skin penetration by 2% α-arbutin after 3 h was 83% greater in group UBD than in group C. The degree of in vivo skin whitening (quantified as the luminosity index) in group UBD significantly increased by 25% after 1 week, 34% after 2 weeks, and then stabilized after 3 weeks at 37% in C57BL/6J mice over a 4-week experimental period. Our results indicate that combined treatment with optimal US and MBs can increase skin permeability so as to enhance α-arbutin delivery to inhibit melanogenesis without damaging the skin in mice.

A novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05% for treatment of epidermal melasma.

Epidermal melasma is a common hyperpigmentation disorder that can be challenging to treat. Although current treatment options for melasma are limited, topical skin-lightening preparations have widely been used as alternatives to hydroquinone. In this prospective, single-arm, open-label study, treatment of epidermal melasma with a novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05% was associated with reductions in Melasma Area and Severity Index (MASI) scores as well as total melasma surface area as measured by medical imaging software. Treatment outcomes including tolerance and safety profiles as well as patient satisfaction and product appreciation showed this novel cosmetic compound may be valuable in the treatment of epidermal melasma.

Opinion of the Scientific Committee on Consumer Safety (SCCS)--Opinion on the safety of the use of ß-arbutin in cosmetic products.

CONCLUSION OF THE OPINION: The SCCS considers the use of ß-arbutin to be safe for consumers in cosmetic products in a concentration up to 7% in face creams provided that the contamination of hydroquinone in the cosmetic formulations remain below 1 ppm. A potential combined use of ß-arbutin and other hydroquinone releasing substances in cosmetic products has not been evaluated in this Opinion.

Novel anti-melanogenic hexapeptoids, PAL-10 and PAL-12.

Diverse compound sources are being explored for de-pigmentation activities to develop novel therapeutic agents or functional cosmetic ingredients for hyper-pigmentation disorders. Peptoids are a class of peptidomimetics whose side chains are appended to the nitrogen atom of the peptide backbone, instead of α-carbon. Peptoids are more durable against proteolysis and are being actively investigated in drug discovery, but rarely studied as cosmetic ingredients. Here, we demonstrated that new hexa-peptoids, PAL-10 and PAL-12, can inhibit melanogenesis in B16F10 melanoma cells, a 3D pigmented human skin model (Neoderm(®)-ME, Tegoscience Co) and zebrafish. Anti-melanogenic effects of PAL-10 or PAL-12 as compared with arbutin, a positive control in B16F10 cells, Neoderm(®)-ME and zebrafish were statistically significant and concentration-dependent anti-melanogenic effects were manifested as determined by image, histology, and melanin contents. Anti-melanogenic effects of PAL-10 appeared to be from enzymatic inhibition of tyrosinase while mRNA expression of melanogenic enzymes was not affected. In conclusion, we demonstrated that PAL-10 and PAL-12 can be used as a new cosmetic ingredient with strong brightening efficacies.

4-n-butylresorcinol, a highly effective tyrosinase inhibitor for the topical treatment of hyperpigmentation.

BACKGROUND: Hyperpigmentary disorders like melasma, actinic and senile lentigines are a major cosmetic concern. Therefore, many topical products are available, containing various active ingredients aiming to reduce melanin production and distribution. The most prominent target for inhibitors of hyperpigmentation is tyrosinase, the key regulator of melanin production. Many inhibitors of tyrosinase are described in the literature; however, most of them lack clinical efficacy. METHODS: We were interested in evaluating the inhibition of skin pigmentation by well-known compounds with skin-whitening activity like hydroquinone, arbutin, kojic acid and 4-n-butylresorcinol. We compared the inhibition of human tyrosinase activity in a biochemical assay as well as inhibition of melanin production in MelanoDerm skin model culture. For some compounds, the in vivo efficacy was tested in clinical studies. RESULTS: Arbutin and hydroquinone only weakly inhibit human tyrosinase with a half maximal inhibitory concentration (IC(50)) in the millimolar range. Kojic acid is 10 times more potent with an IC(50) of approximately 500 µmol/L. However, by far the most potent inhibitor of human tyrosinase is 4-n-butylresorcinol with an IC(50) of 21 µmol/L. In artificial skin models, arbutin was least active with an IC(50) for inhibition of melanin production > 5000 µmol/L. Kojic acid inhibited with an IC(50) > 400 µmol/L. Interestingly, hydroquinone inhibited melanin production in MelanoDerms with an IC(50) below 40 µmol/L, probably due to a mechanism different from tyrosinase inhibition. Again, 4-n-butylresorcinol was the most potent inhibitor with an IC(50) of 13.5 µmol/L. In vivo efficacy of 4-n-butyl-resorcinol was confirmed in clinical studies. Subjects with age spots on the forearm treated twice daily two age spots with a formula containing 4-n-butylresorcinol and two control age spots with the corresponding vehicle. Within 8 weeks, 4-n-butylresorcinol reduced visibly the appearance of age spots, while the control spots showed no improvement. A second study showed that 4-butylresorcinol was more effective than 4-hexylresorcinol and 4-phenylethylresorcinol. CONCLUSION: The present in vitro and in vivo data prove the high inhibitory capacity of 4-n-butylresorcinol on human tyrosinase activity, exceeding by far the potency of hydroquinone, arbutin and kojic acid. The resulting clinical improvement of skin hyperpigmentations reveals 4-n-butylresorcinol as a very valuable active compound for the management of pigmentation disorders.

Topical treatment of hyperpigmentation disorders.

Hyperpigmentation has traditionally been a relatively difficult condition to treat, especially in darker racial ethnic groups. Multiple topical agents available act upon different steps of the pigmentation pathway. We review these topical agents, their mechanisms of action, and their effectiveness as monotherapy and in combination with other compounds. Ultimately, combination therapy is the most efficacious when considering overall depigmentation as well as treatment time required to achieve clinical improvement.