Abstract
RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol (RD))—a skin-whitening ingredient—was reported to induce leukoderma in some consumers. We have examined the biochemical basis of the RD-induced leukoderma by elucidating the metabolic fate of RD in the course of tyrosinase-catalyzed oxidation. We found that the oxidation of racemic RD by mushroom tyrosinase rapidly produces RD-quinone, which gives rise to secondary quinone products. Subsequently, we confirmed that human tyrosinase is able to oxidize both enantiomers of RD. We then showed that B16 cells exposed to RD produce high levels of RD-pheomelanin and protein-SH adducts of RD-quinone. Our recent studies showed that RD-eumelanin—an oxidation product of RD—exhibits a potent pro-oxidant activity that is enhanced by ultraviolet-A radiation. In this review, we summarize our biochemical findings on the tyrosinase-dependent metabolism of RD and related studies by other research groups. The results suggest two major mechanisms of cytotoxicity to melanocytes. One is the cytotoxicity of RD-quinone through binding with sulfhydryl proteins that leads to the inactivation of sulfhydryl enzymes and protein denaturation that leads to endoplasmic reticulum stress. The other mechanism is the pro-oxidant activity of RD-derived melanins that leads to oxidative stress resulting from the depletion of antioxidants and the generation of reactive oxygen radicals.
Highlights
Rhododendrol (RD, Rhododenol®) is a naturally occurring phenolic compound found in plants such as Acer nikoense and Betula platyphylla [1,2,3,4]
In a subsequent study [32], we examined the reactivity of BSA with RD-quinone and RD-cyclic quinone. We found that both quinones bound to BSA effectively through a cysteine residue with yields of about 60%, which is much higher than the binding efficacy (
This suggests that melanoma cells that have survived the cytotoxicity of RD have a much higher activity of the detoxifying mechanism
Summary
Rhododendrol (RD, Rhododenol®) is a naturally occurring phenolic compound found in plants such as Acer nikoense and Betula platyphylla [1,2,3,4]. Preparative HPLC afforded two products, one of which was the expected RD-catechol and the other was found to be the RD-cyclic catechol (Figure 1) This identification led to confirmation of the structures of the oxidation products having absorption maxima near 400 nm and 460 nm as RD-quinone and RD-cyclic quinone, respectively. When the oxidation was stopped by acidification with HClO4, another product appeared as a major product (Figure 2C) This compound could not be isolated because of its high instability, but available evidence suggested it to be RD-hydroxy-p-quinone (Figure 2C). We examined whether RD-quinone and RD-cyclic quinone are able to react with thiols (R-SH) to form R-SH adducts This type of addition reaction, thiol binding, was confirmed for CySH, GSH and N-acetylcysteine [9]. S(+)-RD was more effectively oxidized than L-tyrosine, while R(-)-RD was as effective as L-tyrosine
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