Arbutin

log Kow = -1.35

-1.35

Colorless elongated prisms from moist ethyl acetate

White powder (pure synthetic)

Needles (water + 1)

≥ 10g/100g

Slightly soluble in ethyl ether; insoluble in benzene, chloroform, CS2

Soluble in water and alcohol

199 °C

142 - 143 °C

Crystalizes from water as the monohydrate, mp 158-160 °C; solifidies and melts again at 175 °C. Also reported as unstable form, mp 160.5 °C; stable form, mp 176 °C. Specific optical rotation: -60.66 deg at 20 °C/D (in water). Soluble in hot water or alcohol; slightly soluble in ether. /Methylarbutin/

Specific optical rotation: -60.3 deg at 20 °C/D (in water)

Specific optical rotation: -64 deg at 25 °C/D (3% water)

226.6 Ų [M-H]- [CCS Type: DT; Buffer gas: N2; Ionization: ESI-; Dataset: TOXCAST; Source Identifier: DTXSID7040152]

164.4 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

159.52 Ų [M+Na-2H]- [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

162.95 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 98.6% (137 of 139) of all reports.

Not Classified

Aggregated GHS information provided per 139 reports by companies from 3 notifications to the ECHA C&L Inventory.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Arbutin, the beta-D-glucopyranoside of hydroquinone, is a skin whitening cosmetic ingredient. Compared with arbutin, hydroquinone is a more potent skin lightening agent, but shows cytotoxicity, nephrotoxicity, and genotoxicity. To evaluate whether skin microflora can hydrolyze arbutin to hydroquinone, we measured the hydrolytic activity of the main skin microflora: Staphylococcus epidermidis and Staphylococcus aureus. All strains hydrolyzed arbutin, with activities of 0.16-4.51 nmol/min/mg. The hydrolyzed hydroquinone showed more potent 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity and tyrosinase inhibition than arbutin. These findings suggest that normal skin microflora may increase the skin lightening effect of arbutin due to the antioxidant action of hydroquinone.

...This study ... presents evidence that cotreatment of aloesin and arbutin inhibits tyrosinase activity in a synergistic manner by acting through a different action mechanism. Aloesin or arbutin similarly inhibited enzyme activity of human- and mushroom-tyrosinases with an IC50 value of 0.1 or 0.04 mM, respectively. Lineweaver-Burk plots of the enzyme kinetics data showed that aloesin inhibited tyrosinase activity noncompetitively with a Ki value of 5.3 mM, whereas arbutin did it competitively (Maeda, 1996). We then examined whether cotreatment of these agents inhibits the tyrosinase activity in a synergistic manner. The results showed that 0.01 mM aloesin in the presence of 0.03 mM arbutin inhibited activity of mushroom by 80% of the control value and the reverse was also true. The inhibitory effects were calculated to be synergistic according to the Burgi method. Taken together, we suggest that aloesin along with arbutin inhibits in synergy melanin production by combined mechanisms of noncompetitive and competitive inhibitions of tyrosinase activity.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 4(SRC), determined from a log Kow of -1.35(2) and a regression-derived equation(3), indicates that arbutin is expected to have very high mobility in soil(SRC). Volatilization of arbutin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-19 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Arbutin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-12 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2008).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 4(SRC), determined from a log Kow of -1.35(2) and a regression-derived equation(3), indicates that arbutin is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.2X10-19 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2008).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), arbutin, which has an estimated vapor pressure of 2.3X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase the ambient atmosphere. Particulate-phase arbutin may be removed from the air by wet or dry deposition(SRC). Arbutin does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Arbutin-containing foods include marjoram, pears (fruit, juice, possible adulterant in quince products), Japanese pepper, potatoes (Solanum tuberosum) infected with fungi, foods of Native Canadians, honeys in Italy and Sardinia, and beverages. Significant amounts of arbutin levels were found in wheat products (1-10 ppm), pears (4-15 ppm), and coffee and tea (0.1 ppm)(1).

Uva ursi is generally taken by adults as crushed leaf or powder, an infusion or cold macerations, and fluidextract, providing 400-840 mg arbutin per day. As the dry extract, 100-210 mg arbutin are supplied to the individual. It is also available as a capsule, tea, and tincture. It has been estimated that an individual who drinks up to 3 g of tea from uva ursi leaves (which contain up to 6% HQ glycosides) four times a day consumes ~720 mg arbutin (2.64 mmol; ~12 mg/kg bw). Exposure can also occur through the use of herbal mixtures that contain bearberry or Uva ursi(1).

Arbutin is found in Arctostaphylos uva-ursi (L.) (Bearberry); Vaccinium vitis-idaea var. minus (Cowberry, lingen, lingonberry); Arbutus unedo L. (Arbutus, Strawberry tree); Chimaphila umbellata (L.) (King's Cure, Pipsissewa) and Turnera diffusa (Damiana) (1).

The Koc of arbutin is estimated as 4(SRC), using a log Kow of -1.35(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that arbutin is expected to have very high mobility in soil.

A glucoside found in the leaves of the cranberry, blueberry amd manzanita shrubs, and in the roots, trunks and leaves of most pear species

Arbutin is contained in the leaves of Arctostaphylos uva-ursi (L.) (Bearberry); Vaccinium vitis-idaea var. minus (Cowberry, lingen, lingonberry); Arbutus unedo L. (Arbutus, Strawberry tree) and Turnera diffusa (Damiana) at 120,000; 90,000; 270,000 and 7,000 ppm, respectively(1). It is found in the Chimaphila umbellata (L.) (King's Cure, Pipsissewa) plant at 75,000 ppm(1).

/GENOTOXICITY/ Although arbutin is a natural product and widely used as an ingredient in skin care products, its effect on the gene expression level of human skin with malignant melanoma cells is rarely reported. We aim to investigate the genotoxic effect of arbutin on the differential gene expression profiling in A375 human malignant melanoma cells through its effect on tumorigenesis and related side-effect. The DNA microarray analysis provided the differential gene expression pattern of arbutin-treated A375 cells with the significant changes of 324 differentially expressed genes, containing 88 up-regulated genes and 236 down-regulated genes. The gene ontology of differentially expressed genes was classified as belonging to cellular component, molecular function and biological process. In addition, four down-regulated genes of AKT1, CLECSF7, FGFR3, and LRP6 served as candidate genes and correlated to suppress the biological processes in the cell cycle of cancer progression and in the downstream signaling pathways of malignancy of melanocytic tumorigenesis.

/ALTERNATIVE and IN VITRO TESTS/ To study the effects of aloesin and arbutin on normal cultured human melanocytes in synergetic method. Building up the system of cultured human melanocytes. The cultured melanocytes in vitro were treated with the mixture of aloesin and arbutin. The cell viability and tyrosinase activity was measured by MTT assay, utilization of L-Dopa as the substrate respectively; melanin content was measured by image analysis system. Furthermore, the effects of the mixture on melanocytes were compared with that of aloesin and arbutin. The mixture of aloesin and arbutin showed an inhibition on tyrosinase activity of human melanocytes and reduced significantly melanin content. Between the mixture and the single use of aloesin or arbutin, there is significant difference (P<0.05). On the other hand, the mixture has little influence on melanocytes viability and there is negative significance. The mixture of aloesin and arbutin can significantly inhibit the tyrosinase activity and melanogenesis of cultured human melanocytes. It showed the effects of aloesin and arbutin in a synergistic manner.

/ALTERNATIVE and IN VITRO TESTS/ To discover safe and effective topical skin-lightening agents ... alkyl esters of the natural product gentisic acid (GA) ... , four putative tyrosinase inhibitors, /were evaluated/ utilizing mammalian melanocyte cell cultures and cell-free extracts. Desirable characteristics include the ability to inhibit melanogenesis in cells (IC50 less than 100 ug/mL) without cytotoxicity, preferably due to tyrosinase inhibition. Of the six esters synthesized, the smaller esters (e.g. methyl and ethyl) were more effective enzyme inhibitors (IC50 approximately 11 and 20 ug/mL, respectively). For comparison, hydroquinone (HQ), a commercial skin "bleaching" agent, was a less effective enzyme inhibitor (IC50 approximately 72 ug/mL), and was highly cytotoxic to melanocytes in vitro at concentrations substantially lower than the IC50 for enzymatic inhibition. Kojic acid was a potent inhibitor of the mammalian enzyme (IC50 approximately 6 ug/mL), but did not reduce pigmentation in cells. Both arbutin and magnesium ascorbyl phosphate were ineffective in the cell-free and cell-based assays... .

Arbutin's production and use as oxidation inhibitor, polymerization inhibitor, color stabilizer in photography, intermediate(1), an ingredient in cosmetics(2) and as an herbal medication(3) may result in its release to the environment through various waste streams(SRC).

An estimated BCF of 3 was calculated in fish for arbutin(SRC), using a log Kow of -1.35(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for arbutin is estimated as 1.2X10-19 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that arbutin is expected to be essentially nonvolatile from water surfaces(2). Arbutin's Henry's Law constant indicates that volatilization from moist soil surfaces may not occur(SRC). Arbutin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-12 mm Hg(SRC), determined from a fragment constant method(3).

/GENOTOXICITY/ Arbutin (hydroquinone-beta-D-glucopyranoside) is present in various food plants. Its aglycone, hydroquinone, is mutagenic and carcinogenic. We investigated whether hydroquinone may be released under conditions encountered in the human gastrointestinal tract. Arbutin was stable in artificial gastric juice. Fecal slurries from nine human subjects completely converted arbutin (2 mM) into hydroquinone. Four of nine representative human intestinal species investigated, namely Eubacterium ramulus, Enterococcus casseliflavus, Bacteroides distasonis, and Bifidobacterium adolescentis, deglycosylated arbutin at rates of 21.08, 16.62, 8.43 and 3.59 nmol/min/(mg protein), respectively. In contrast, homogenates from small intestinal mucosa and cytosolic fractions from colon mucosa deglycosylated arbutin at substantially lower rates: 0.50 and 0.09 nmol/min/(mg protein), respectively. Arbutin, unlike hydroquinone, did not induce gene mutations in Chinese hamster V79 cells in the absence of an activating system. However, in the presence of cytosolic fractions from E. ramulus or B. distasonis, arbutin was strongly mutagenic. Cytosolic fraction from Escherichia coli, showing no arbutin glycosidase activity, was not able to activate arbutin in this model system. The release of the proximate mutagen hydroquinone from arbutin by intestinal bacteria in the immediate vicinity of the colon mucosa may pose a potential risk.

The rate constant for the reaction of arbutin with hydroxyl radicals in aqueous solutions is 3.1X10+9 L/mol-sec(1); this corresponds to an aquatic half-life of 260 days at an aquatic concentration of 1X10-17 hydroxyl radicals per liter(2). Arbutin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Arbutin does not contain chromophores that absorb at wavelengths >290 nm(3) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

At non-toxic concentrations, arbutin inhibited the activity of tyrosinase in cultured human keratinocytes, while having minimal effect on the expression of tyrosinase mRNA or the synthesis of the enzyme. α-Arbutin produced a concentration-dependent inhibition of melanin synthesis of human melanoma cells, HMV-II. No inhibitory effect on HMV-II cell growth was seen at concentrations lower than 1.0 mM. At concentrations of 0.5 mM of arbutin, tyrosinase activity was reduced to 60% of that in non-treated cells. The addition of arbutin blocked and inhibited α-MSH-stimulated melanogenesis in B16 melanoma cells, brownish guinea pig, and human skin tissue. In a pilot study of healthy male adults exposed to UV B irradiation, topical administration of arbutin inhibited UV-induced nuclear factor-kappaB activation in human keratinocytes. In mouse skin, arbutin counteracted oxidative stress induced by 12-O-tetradecanoylphorbol-13-acetate.

Arbutin is a hydroquinone glycoside, however the hydroquinone moiety is not solely responsible for the de-pigmentating actions of arbutin. It acts as a competitive inhibitor of tyrosinase enzyme by acting on the L-tyrosine binding site to suppress melanogenesis and mediate its de-pigmenting actions on human skin. Tyrosinase is an enzyme involved in the regulation of rate-limiting steps during the synthesis of melanin; it regulates the conversion of L-tyrosine into L-dopa, and subsequent conversion of L-dopa to L-dopaquinone. Via inhibition of tyrosinase activity in a concentration-dependent manner, arbutin attenuates the production of melanin in melanocytes. While most studies suggest that arbutin has negligible effect on the tyrosinase mRNA expression, a study assessing the effect of arbutin on melanocyte differentiation inducement system using ES cells propose that arbutin may also downregulate the expression of tyrosinase in addition to its inhibitory action on the enzyme. The contradictory findings across studies may be due to previous studies using terminally-differentiated melanocytes and melanoma cells.

...This study ... presents evidence that cotreatment of aloesin and arbutin inhibits tyrosinase activity in a synergistic manner by acting through a different action mechanism. Aloesin or arbutin similarly inhibited enzyme activity of human- and mushroom-tyrosinases with an IC50 value of 0.1 or 0.04 mM, respectively. Lineweaver-Burk plots of the enzyme kinetics data showed that aloesin inhibited tyrosinase activity noncompetitively with a Ki value of 5.3 mM, whereas arbutin did it competitively (Maeda, 1996). We then examined whether cotreatment of these agents inhibits the tyrosinase activity in a synergistic manner. The results showed that 0.01 mM aloesin in the presence of 0.03 mM arbutin inhibited activity of mushroom by 80% of the control value and the reverse was also true. The inhibitory effects were calculated to be synergistic according to the Burgi method. Taken together, we suggest that aloesin along with arbutin inhibits in synergy melanin production by combined mechanisms of noncompetitive and competitive inhibitions of tyrosinase activity.

Arbutin is readily susceptible to hydrolysis in dilute acids to yield D-glucose and hydroquinone. It is expected that orally administered arbutin is easily hydrolyzed to free hydroquinone molecules by stomach acid. Hydroquinone is further metabolized into the main metabolites, hydroquinone glucuronide and hydroquinone sulfate.

Arbutin was found to be extensively absorbed from the gastrointestinal tract where it is primarily converted to hydroquinone.

During the first 4 hours following ingestion of a single dose of 210 mg arbutin in healthy volunteers, 224.5 μmol/L hydroquinone glucuronide and 182 μmol/L of hydroquinone sulfate were recovered in the urine.

No pharmacokinetic data available.

No pharmacokinetic data available.

The urinary excretion of arbutin metabolites was examined in a randomized crossover design in 16 healthy volunteers after the application of a single oral dose of bearberry leaves dry extract (BLDE). There were two groups of application using either film-coated tablets (FCT) or aqueous solution (AS). The urine sample analysis was performed by a validated HPLC coolarray method (hydroquinone) and a validated capillary electrophoresis method (hydroquinone-glucuronide, hydroquinone-sulfate). The total amounts of hydroquinone equivalents excreted in the urine from BLDE were similar in both groups. With FCT, 64.8% of the arbutin dose administered was excreted; with AS, 66.7% was excreted (p = 0.61). The maximum mean urinary concentration of hydroquinone equivalents was a little higher and peaked earlier in the AS group versus the FCT group, although this did not reach statistical significance (Cur max = 1.6893 umol/mL vs. 1.1250 umol/mL, p = 0.13; tmax (t midpoint) = 3.60 h vs. 4.40 hr, p = 0.38). The relative bioavailability of FCT compared to AS was 103.3% for total hydroquinone equivalents. There was substantial intersubject variability. No significant differences between the two groups were found in the metabolite patterns detected (hydroquinone, hydroquinone-glucuronide, and hydroquinone-sulfate).

To study the effects of aloesin and arbutin on normal cultured human melanocytes in synergetic method. Building up the system of cultured human melanocytes. The cultured melanocytes in vitro were treated with the mixture of aloesin and arbutin. The cell viability and tyrosinase activity was measured by MTT assay, utilization of L-Dopa as the substrate respectively; melanin content was measured by image analysis system. Furthermore, the effects of the mixture on melanocytes were compared with that of aloesin and arbutin. The mixture of aloesin and arbutin showed an inhibition on tyrosinase activity of human melanocytes and reduced significantly melanin content. Between the mixture and the single use of aloesin or arbutin, there is significant difference (P<0.05). On the other hand, the mixture has little influence on melanocytes viability and there is negative significance. The mixture of aloesin and arbutin can significantly inhibit the tyrosinase activity and melanogenesis of cultured human melanocytes. It showed the effects of aloesin and arbutin in a synergistic manner.

In cosmetics as skin lightening agent

Oxidation inhibitor, polymerization inhibitor, color stabilizer in photography, intermediate

Herbal remedy

Arbutin has been sugggested as a potential antitussive.

Use (kg; approx.) in Germany (2009): >2500

Occurs as the monohydrate

Available commercially in both natural and synthetic forms

...The upland cranberry extract ... bearberry /Arctostaphylos uva-ursi (L.) Spreng/ ... is standardized to contain 20% arbutin. In the body, arbutin breaks down into hydroquinone, a compound recognized for its role in urinary tract function