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Exogenous Ochronosis by Hydroquinone is not caused by Inhibition of Homogentisate Dioxygenase but potentially by Tyrosinase-catalyzed Metabolism of Hydroquinone.

Shosuke Ito,L. Kolbe,G. Weets,Tamara Rogers,Caroline Bushdid,Tomoko Nishimaki-Mogami,Hitomi Tanaka,T. Passeron,Makoto Ojika,Kazumasa Wakamatsu

Published 2025 in British Journal of Dermatology

ABSTRACT

BACKGROUND Hydroquinone (HQ) is widely used for its hypopigmenting effects in treating hyperpigmentation disorders. However, its topical application has been linked to adverse effects, notably exogenous ochronosis (EO), raising concerns about its safety and mechanisms of action. OBJECTIVE This study aims to elucidate the metabolic pathway of HQ in human melanocytes and clarify the role of tyrosinase in the development of EO. METHODS We conducted an in vitro investigation utilizing human tyrosinase to analyze the metabolism of HQ. The study involved assessing the oxidation of HQ in the presence of L-dopa and L-cysteine, measuring the production of dopaquinone and its subsequent derivatives, including 2-S-cysteinyl-HQ (Cys-HQ) and HQ-pheomelanin (HQ-PM). RESULTS Our findings demonstrate that human tyrosinase effectively oxidizes HQ primarily via dopaquinone, with L-cysteine facilitating the formation of Cys-HQ. Further oxidation of Cys-HQ leads to the production of HQ-PM. Notably, the results indicate that tyrosinase activity is crucial for the induction of EO by HQ. Additionally, while high-molecular weight HQ derivatives may remain within melanosomes, low-molecular weight metabolites can penetrate the dermis, potentially triggering the polymerization of ochronotic particles similar to those observed in EO. CONCLUSION This study concludes that tyrosinase plays a significant role in HQ-induced EO, suggesting that HQ acts as a "pseudo" substrate for this enzyme. The findings highlight the importance of using tyrosinase inhibitors to reduce the risk of EO, while cautioning against other melanogenesis inhibitors that may exhibit similar side effects.Ochronosis is the most feared adverse effect of hydroquinone (HQ) treatment. In HQ treated skin, both regular melanin and hydroquinone-derived melanin are synthesized, deposited on PMEL fibrils within melanosomes of melanocytes (1) and eventually shed from the skin surface by desquamation. However, low-molecular weight HQ derivatives are sufficiently small to diffuse into the surrounding dermal tissue (3), bind to photo-damaged collagen fibers, and start the formation of ochronotic particles (3).

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