Rhododendrol

Rhododendrol (RD) also called 4-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. . 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reportedly caused skin depigmentation in consumers using RD-containing skin-brightening cosmetics, the cosmetics were withdrawn from the market.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 . It is now well established that rhododendrol is a potent tyrosinase inhibitor. Rhododendrol (RD) also called 4-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. . 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reportedly caused skin depigmentation in consumers using RD-containing skin-brightening cosmetics, the cosmetics were withdrawn from the market.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 . It is now well established that rhododendrol is a potent tyrosinase inhibitor. 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 . The compound can also be prepared by reducing raspberry ketone (4-(4-hydroxyphenyl)-2- butanone) with Raney nickel in EtOH . 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 . 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) . However, another study stated that there was no ROS detected in the with rhododendrol-treated melanocytes, but a tyrosinase-dependent accumulation of endoplasmic reticulum stress and activation of the apoptotic pathway . 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 . 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) . Presence of o-quinones can lead to cytotoxicity via the production of reactive oxygen species (ROS) or by the binding to enzymes or DNA . When rhododendrol is metabolised via the tyrosinase-catalysed oxidation RD-quinone will be formed . 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 . 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 . Caspase proteins are crucial mediators of apoptosis, with caspase-3 and caspase-8 being death proteases . Considering melanocytes are responsible for skin colour, apoptosis of these cells causes the colour of the skin to vanish . 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 . 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 .