Hydroquinone has long been used as the gold standard treatment for hyperpigmentation, yet despite its effectiveness, it has been associated with a severe adverse reaction known as exogenous ochronosis, where blue-black discoloration develops after long-term topical use. For decades, this condition was believed to occur through the same mechanism as endogenous ochronosis seen in alkaptonuria, a genetic disorder caused by mutations in homogentisate 1,2-dioxygenase (HGD) that lead to the accumulation of homogentisic acid.
However, a new international collaborative study made available online on July 15, 2025, and published in Volume 193, Issue 5 of the British Journal of Dermatology on November 1, 2025, demonstrates that this long-standing hypothesis is incorrect. This study was led by Emeritus Professor Shosuke Ito from the Institute for Melanin Chemistry, Fujita Health University, Japan, in collaboration with Ludger Kolbe from Beiersdorf AG, Germany; Tomoko Nishimaki-Mogami, National Institute for Health Sciences, Japan; and Thierry Passeron from the University Côte d’Azur, France. They showed that HGD is not expressed in human skin and thus cannot be inhibited by hydroquinone in any biologically meaningful way. Topically applied hydroquinone also cannot reach the liver, where HGD is normally active, in concentrations high enough to interfere with its function.
Computational docking simulations further confirmed that hydroquinone binds poorly to HGD compared to natural substrates and known inhibitors, contradicting earlier assumptions that hydroquinone-induced ochronosis results from HGD inhibition. Dr. Ito said, “To investigate the underlying mechanisms of exogenous ochronosis, we examined both the potential inhibition of HGD and the metabolism of hydroquinone catalyzed by tyrosinase.”
The research team reveals a completely different and previously underappreciated mechanism that human tyrosinase plays a central role in metabolizing hydroquinone into reactive intermediates that can cause dermal pigmentation. Using biochemical assays, high-performance liquid chromatography, melanocyte cultures, and tyrosinase-expressing human cells, the researchers showed that tyrosinase rapidly oxidizes hydroquinone in the presence of L-DOPA. This reaction proceeds through a redox exchange, forming p-benzoquinone and downstream metabolites such as 2-S-cysteinylhydroquinone and hydroquinone-pheomelanin (the BQ pathway in the Figure). These compounds are produced far more efficiently than the minor hydroxylation reaction previously assumed to be responsible for toxicity (the HBQ pathway in the Figure).
The study also demonstrated that these hydroquinone-derived metabolites accumulate differently depending on molecular size. High-molecular-weight pigments remain within melanosomes, but low-molecular-weight intermediates are capable of diffusing out of the melanosome and into the dermis. There, especially in chronically sun-damaged skin where collagen fibers are already compromised, these metabolites can bind to dermal proteins and undergo polymerization, forming ochronotic pigments that closely resemble those observed in endogenous ochronosis.
The findings explain several clinical observations: exogenous ochronosis occurs predominantly in sun-exposed areas, develops only after long-term use, and appears exclusively in skin regions where tyrosinase is active. Areas lacking active melanocytes, such as vitiligo patches, remain unaffected even when hydroquinone is applied, reinforcing that tyrosinase activity is essential to initiating the pigment-forming cascade. This understanding significantly changes the landscape of hyperpigmentation treatment. Because hydroquinone acts as a pseudo-substrate for tyrosinase, its long-term metabolism in melanocytes produces harmful oxidative byproducts capable of generating dermal pigmentation.
The study recommends prioritizing true tyrosinase inhibitors like Thiamidol®, butylresorcinol, hexylresorcinol, and kojic acid for hyperpigmentation treatment. In contrast, apparent pigmentation reducers that serve as tyrosinase substrates—such as rhododendrol and raspberry ketone—carry similar risks and warrant avoidance in topicals. "Compounds that act as substrates for tyrosinase should be avoided in topical products, while highly effective and selective tyrosinase inhibitors are considered safe for use," concluded Dr. Ito.
According to the authors, a clearer understanding of the metabolic steps leading to ochronosis will guide the development of safer and more effective depigmenting agents. By identifying tyrosinase and not HGD, as the key initiator of hydroquinone-induced ochronosis, this research provides a crucial scientific foundation for designing next-generation skincare ingredients that reduce pigmentation without risking long-term dermal damage.
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Reference
DOI: 10.1093/bjd/ljaf273
About Fujita Health University
Fujita Health University (FHU) is a private medical university located in Aichi, Japan. Established in 1964, it houses one of the largest university hospitals in Japan. It's 900 member faculty provides diverse learning and research opportunities to medical students worldwide. Guided by its founding philosophy of "Our creativity for the people" Fujita Health University believes that it's students can shape the future through creativity and innovation. FHU has earned global recognition, ranking eighth among all universities and second among private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. The university ranked fourth worldwide in the 2024 THE University Impact Rankings for contributions to the "Good Health and Well-being" SDG (Sustainable Development Goals) of the United Nations (UN). In June 2021, the university made history as the first Japanese institution to host the THE Asia Universities Summit. In 2024, Fujita Health University was awarded the Forming Japan’s Peak Research Universities (J-PEAKS) Program by the Japanese government to establish an innovative academic drug discovery ecosystem and hub of a multi-university consortium for research and education.
Website: https://www.fujita-hu.ac.jp/en/index.html
About Emeritus Professor Shosuke Ito from Fujita Health University
Dr. Shosuke Ito is an Emeritus Professor at the Institute for Melanin Chemistry, Fujita Health University, Japan. A leading authority on melanin biochemistry, he has spent decades investigating melanogenesis pathways, pigment disorders, and the chemical behavior of phenolic compounds in human skin. His laboratory specializes in analytical chemistry of melanin and tyrosinase-related reactions, contributing foundational insights into pigmentation biology. Over the past decade, Dr. Ito and his collaborators have focused on how synthetic and natural phenolic compounds undergo tyrosinase-mediated metabolism, revealing mechanisms underlying adverse skin reactions such as leukoderma and exogenous ochronosis.
Funding information
This research was supported, in part, by a Japan Health, Labour and Welfare Policy Research Grant (19KC2005) given to Shosuke Ito and Tomoko Nishimaki-Mogami.
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