Study clarifies hydroquinone’s role in ochronosis

Tyrosinase (Tyr) catalyzes hydroquinone (HQ) oxidation via two main pathways. The HBQ pathway directly oxidizes HQ to 2-hydroxy-1,4-benzoquinone (HBQ), which dimerizes and forms hydroquinone-eumelanin (HQ-EM). The BQ pathway involves dopaquinone (DQ)-mediated redox exchange producing p-benzoquinone (BQ), which reacts with cysteine (Cys) to form 2-S-cysteinylhydroquinone (Cys-HQ) and further oxidizes to hydroquinone-pheomelanin (HQ-PM). These pathways illustrate the enzymatic formation of reactive metabolites linked to exogenous ochronosis. Image courtesy Emeritus Professor Shosuke Ito from Fujita Health University, Japan

A new study reveals tyrosinase plays a role in the metabolism of hydroquinone into byproducts that lead to the permanent pigmentation of exogenous ochronosis. This finding overturns the long-held belief that the pigment disorder is driven by inhibition of homogentisate 1,2-dioxygenase (HGD).

The study was published in the British Journal of Dermatology.

In a press release, the authors note that hydroquinone has long been the gold standard for treating hyperpigmentation. However, long-term topical use has been associated with permanent blue-black discoloration. For decades, exogenous ochronosis was believed to occur through the same mechanism as endogenous ochronosis seen in alkaptonuria, a genetic disorder caused by mutations in HGD that lead to the accumulation of homogentisic acid.

However, the new study demonstrates that this long-standing hypothesis is incorrect. This research was led by Emeritus Professor Shosuke Ito, PhD, from the Institute for Melanin Chemistry, Fujita Health University, Japan. Dr. Ito and his colleagues demonstrated that HGD is not expressed in human skin and so cannot be inhibited by topical hydroquinone in any biologically meaningful way. Topically applied hydroquinone also cannot reach the liver, where HGD usually is active, in concentrations high enough to interfere with the enzyme’s 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. In the release, 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 identified a different, previously underappreciated mechanism human tyrosinase plays a central role in, through which hydroquinone is metabolized 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. These compounds are produced far more efficiently than the minor hydroxylation reaction previously assumed to be responsible for exogenous ochronosis.

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 fibres are already compromised, these metabolites can bind to dermal proteins and polymerize, forming ochronotic pigments that closely resemble those observed in endogenous ochronosis.

The findings explain several clinical observations, the authors note. In particular, 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 the notion that tyrosinase activity is essential for initiating the pigment-forming cascade.

This understanding significantly changes the landscape of hyperpigmentation treatment, the authors say. Because hydroquinone acts as a pseudo-substrate for tyrosinase, its long-term metabolism in melanocytes produces harmful oxidative byproducts that can generate dermal pigmentation.

With this new information, the researchers recommend prioritizing true tyrosinase inhibitors such as 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, more effective depigmenting agents. By identifying tyrosinase, rather than 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.

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.

---

Happy holidays from Derm.city

Derm.city would like to send a big thank you to our readers for your attention and support during the past year. This newsletter will be taking a break for the holiday season, and will return on Monday, January 12, 2026.

We wish you and your families a happy and safe season.

See you next year.