Names | |
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IUPAC name 4-[(3R)-3-hydroxybutyl]phenol | |
Other names Rhododenol, RD, 4-(4-hydroxyphenyl)-2-butanol, (-)-Betuligenol, (R)-Frambinol, 4-Hydroxy-α-methyl-benzenepropanol | |
Identifiers | |
3D model (JSmol) | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard | 100.237.232 |
EC Number |
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PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C10H14O2 | |
Molar mass | 166.22 g/mol |
Appearance | White solid powder |
Density | 1.1±0.1 g/cm3 |
Melting point | 68-71 °C |
Boiling point | 315.4±17.0 °C at 760 mmHg |
Hazards | |
Occupational safety and health (OHS/OSH): | |
Main hazards | cytotoxicity |
GHS labelling: | |
Warning | |
H302, H319 | |
P270, P280, P301+P312, P305+P351+P338, P330, P337+P313, P501 | |
Flash point | 153.4±15.5 °C |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Rhododendrol (RD) also called 4-[(3R)-3-hydroxybutyl]phenol (systemic name), is an organic compound with the formula C10H14O2. It is a naturally occurring ingredient present in many plants, such as the Rhododendron. [1] The phenolic compound was first developed in 2010 as a tyrosinase inhibitor for skin-lightening cosmetics. In 2013, after rhododendrol reportedly caused skin depigmentation in consumers using RD-containing skin-brightening cosmetics, the cosmetics were withdrawn from the market. The skin condition, caused by RD, is called RD-induced leukoderma. Rhododendrol exerts melanocyte cytotoxicity via a tyrosinase-dependent mechanism. It has been shown to impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45. [2] It is now well established that rhododendrol is a potent tyrosinase inhibitor. [3] [4]
Rhododendrol occurs as the glucoside rhododendrin in leaves of the Rhododendron (Ericacae), and it naturally occurs as a phenolic compound in plants such as Acer nikoense , Betula platyphylla, and the Chinese red birch Betula Alba. The compound can be obtained from alkylation of phenols (C6H5OH). The molecule has a para-substituted structure, and one chiral center. Also, the compound has a natural charge.
There are several ways to synthesise rhododendrol. First, the synthesis can be achieved in six steps from benzaldehyde. The key reactions in this method include aldol condensation and trichloroacetimidate glycosylation. [5] The compound can also be prepared by reducing raspberry ketone (4-(4-hydroxyphenyl)-2- butanone) with Raney nickel in EtOH. [6] In addition, Rhododendrol can be synthesised from p-coumaric acid. This pathway involves reduction of the aliphatic double bond present in p-coumaric acid.
The mechanism of action of rhododendrol has been investigated in multiple studies which revealed that RD competes with tyrosine for hydroxylation by tyrosinase and interferes with melanin synthesis. [7] [8] [9] First, RD is catalysed by tyrosinase to produce toxic metabolites as RD-cyclic catechol. These reactive metabolites cause damage to the melanocytes. There is still uncertainty, however, how the metabolites result in melanocyte damage.
A previous report reported that the melanocyte toxicity of rhododendrol is caused by the production of cytotoxic reactive oxygen species (ROS). [2] However, another study stated that there was no ROS detected in the rhododendrol-treated melanocytes, but a tyrosinase-dependent accumulation of endoplasmic reticulum stress and activation of the apoptotic pathway. [10] [9] Even though there is still no full agreement on the exact mechanism of action, it is suggested that the mechanism of RD-induced leukoderma closely resembles the mechanism displayed in the figure below (Suggested mechanism of Rhododendrol.png).
In some individuals, a T-cell response is observed. The melanocyte cell lysates may sensitise T-cells, and the immunised cytotoxic T-lymphocytes (specific to Melan A, which is a melanocytic differentiation marker) may enhance the RD-induced leukoderma or evoke vitiligo-like lesions on the non-applied skin. [7]
Rhododendrol is metabolised via tyrosinase-catalysed oxidation. Therefore, the enzyme tyrosinase is necessary for the oxidation of rhododendrol. Tyrosinase regularly plays an essential role in the production of melanocytes called the melanogenesis. After oxidation of rhododendrol by the tyrosinase enzyme, several kinds of phenols and catechols are formed. These phenols and catechols together form ortho-quinones (o-quinones). [2] Presence of o-quinones can lead to cytotoxicity via the production of reactive oxygen species (ROS) or by the binding to enzymes or DNA. [3]
When rhododendrol is metabolised via the tyrosinase-catalysed oxidation RD-quinone will be formed. [1] This formation gives rise to the formation of secondary quinones. As described in the mechanisms of action, the presence of quinones could cause cytotoxicity to melanocytes by the production of ROS or by binding to DNA and enzymes.
Considering the use of rhododendrol is prohibited since 2013, the knowledge about the side effects rhodendodrol causes is limited. As stated above, the main known adverse effect of rhododendrol is melanocyte toxicity. [11] Melanocytes are melanin-producing cells, primarily responsible for skin colour. Melanocyte toxicity induces apoptosis of the cell, causing the melanocytes to die. This is due to an increased expression of caspase-3 and caspase-8. [1] Caspase proteins are crucial mediators of apoptosis, with caspase-3 and caspase-8 being death proteases. [12] Considering melanocytes are responsible for skin colour, apoptosis of these cells causes the colour of the skin to vanish. [13] This disease caused by rhododendrol is called leukoderma. Leukoderma, also known as vitiligo, is a skin disease characterized by patches of the skin losing their pigment. This rhododendrol-induced depigmentation can be either long-term and short term. In most cases, repigmentation and cessation of further depigmentation occur after discontinuing the exposure to the substance. However, some patients develop vitiligo vulgaris through the spread of depigmentation into non-exposed areas. This only occurs after severe chemical damage. [14] In addition, rhododendrol not only causes melanocytes to go into apoptosis but it also inhibits melanogenesis. Meaning that the use of rhododendrol not only causes melanocytes to die, but also prevents the development of new melanocytes. [1]
The relevance of particular information in (or previously in) this article or section is disputed .(June 2019) |
Various studies have shown that there is more than one mechanism by which rhododendrol can have a toxic effect. This toxic effect of rhododendrol is found in the melanocytes, which gives rise to skin depigmentation.
Rhododendrol can have a toxic effect via the production of reactive oxygen species (ROS). This will cause an impairment in the further development of melanocytes in the skin. Impairment is caused by upregulation of the GADD45 gene. A study of Kim et al. showed that the production of ROS, which gives rise to more production of GADD45, is already found at low concentrations of rhododendrol. At the time that rhododendrol was used in cosmetic products, it contained concentrations of 2%. The study of Kim et al. suggests that the production of reactive oxygen species at low concentrations may have contributed to the development of leukoderma in users of these cosmetic products. [15]
The study of Ito et al. showed that rhododendrol exerts its toxic effect in the melanocytes via tyrosinase-dependent mechanisms. This tyrosinase enzyme breaks rhododendrol down into the following reactive metabolites: RD-quinone and RD-cyclic quinone. [16] These reactive metabolites can bind to proteins which contain a thiol-group [17] or it can form radicals. These radicals are toxic to the melanocytes as it causes auto-oxidation of the cells. [16] Auto-oxidation, in turn, causes oxidative stress to cells, which will impair the natural growth and function of the melanocytes.
Rhododenol and raspberry ketone impair the regular proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45. [15]
The effect of rhododendrol (4-(4-hydroxyphenyl)-2-butanol) is measured in mice as well as in guinea pigs. [18] [19] These studies were performed to elucidate the aetiology of RD-induced leukoderma. The data of these studies revealed that the amount of RD applied to the skin is highly relevant considering that high doses of RD are required in order to cause cytotoxicity. This finding is contrary to the results presented in the study of Kim et al., which is performed in humans. Furthermore, the animal studies enlightened the importance of the ER-stress response. It is suggested that the activity of the ER-stress response may determine whether melanocytes survive or die. Also, the study of Abe et al. revealed that the autophagy pathway may be involved in the resistance to the cytotoxicity of RD. [18]
Since the biochemical and histological characteristics of the used mice in the animal studies (hairless hk14-SCF Tg mice) closely resembled the characteristics of the human skin, these newly generated mice could be used as experimental animal models to investigate chemical vitiligo further.
Melanin is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes.
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer of the skin's epidermis, the middle layer of the eye, the inner ear, vaginal epithelium, meninges, bones, and heart found in many mammals and birds. Melanin is a dark pigment primarily responsible for skin color. Once synthesized, melanin is contained in special organelles called melanosomes which can be transported to nearby keratinocytes to induce pigmentation. Thus darker skin tones have more melanosomes present than lighter skin tones. Functionally, melanin serves as protection against UV radiation. Melanocytes also have a role in the immune system.
Vitiligo is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure. Treatment options include topical medications, light therapy, surgery and cosmetics. The condition can show up on any skin type as a light peachy color and can appear on any place on the body in all sizes. The spots on the skin known as vitiligo are also able to “change” as spots lose and regain pigment; they will stay in relatively the same areas but can move over time and some big patches can move through the years but never disappear overnight.
Hypopigmentation is characterized specifically as an area of skin becoming lighter than the baseline skin color, but not completely devoid of pigment. This is not to be confused with depigmentation, which is characterized as the absence of all pigment. It is caused by melanocyte or melanin depletion, or a decrease in the amino acid tyrosine, which is used by melanocytes to make melanin. Some common genetic causes include mutations in the tyrosinase gene or OCA2 gene. As melanin pigments tend to be in the skin, eye, and hair, these are the commonly affected areas in those with hypopigmentation.
Melasma is a tan or dark skin discoloration. Melasma is thought to be caused by sun exposure, genetic predisposition, hormone changes, and skin irritation. Although it can affect anyone, it is particularly common in women, especially pregnant women and those who are taking oral or patch contraceptives or hormone replacement therapy medications.
Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper–Mason pathway. Firstly, the hydroxylation of a monophenol and secondly, the conversion of an o-diphenol to the corresponding o-quinone. o-Quinone undergoes several reactions to eventually form melanin. Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from tyrosine by oxidation. It is found inside melanosomes which are synthesized in the skin melanocytes. In humans, the tyrosinase enzyme is encoded by the TYR gene.
Skin whitening, also known as skin lightening and skin bleaching, is the practice of using chemical substances in an attempt to lighten the skin or provide an even skin color by reducing the melanin concentration in the skin. Several chemicals have been shown to be effective in skin whitening, while some have proven to be toxic or have questionable safety profiles. This includes mercury compounds which may cause neurological problems and kidney problems.
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β-arbutin, also known by its International Nomenclature of Cosmetic Ingredients (INCI) name, arbutin, is a glycosylated derivative of hydroquinone. β-Arbutin is naturally present in the leaves and bark of a variety of plants, notably the bearberry plant, Arctostaphylos uva-ursi. Utilized as a biosynthetic active ingredient in topical treatments for skin lightening, β-arbutin is aimed at addressing hyperpigmentation issues. Its mechanism of action involves inhibiting the activity of tyrosinase, an essential enzyme for melanin synthesis in the human skin, thereby leading to a reduction in hyperpigmentation. It is important to distinguish β-arbutin from its structurally similar stereoisomer, α-arbutin, which exhibits similar effects in clinical applications.
Betulinic acid is a naturally occurring pentacyclic triterpenoid which has antiretroviral, antimalarial, and anti-inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase. It is found in the bark of several species of plants, principally the white birch from which it gets its name, same as the bracket fungus Fomitopsis betulina, but also the ber tree, selfheal, the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas, a member of the persimmon family, Tetracera boiviniana, the jambul, flowering quince, rosemary, and Pulsatilla chinensis.
Polyphenol oxidase, an enzyme involved in fruit browning, is a tetramer that contains four atoms of copper per molecule.
Cephaloridine is a first-generation semisynthetic derivative of antibiotic cephalosporin C. It is a Beta lactam antibiotic, like penicillin. Its chemical structure contains 3 cephems, 4 carboxyl groups and three pyridinium methyl groups.
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Postinflammatory hypopigmentation is a cutaneous condition characterized by decreased pigment in the skin following inflammation of the skin.
Arsenic biochemistry refers to biochemical processes that can use arsenic or its compounds, such as arsenate. Arsenic is a moderately abundant element in Earth's crust, and although many arsenic compounds are often considered highly toxic to most life, a wide variety of organoarsenic compounds are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous organisms. This pattern is general for other related elements, including selenium, which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some aquifers, potentially affecting many millions of people via biochemical processes.
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Glyceryl octyl ascorbic acid (GO-VC) is an amphipathic derivative of vitamin C consisting of two ether linkages: a 1-octyl at position 2 and a glycerin at position 3. The chemical name is 2-glyceryl-3-octyl ascorbic acid. The isomer in which these two groups are swapped is also known.
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