Exogenous ochronosis by hydroquinone is not caused by inhibition of homogentisate dioxygenase but potentially by tyrosinase-catalysed metabolism of hydroquinone

BACKGROUND: Hydroquinone is widely used for its hypopigmenting effects in treating hyperpigmentation disorders. However, its topical application has been linked to adverse effects, notably exogenous ochronosis, raising concerns about its safety and mechanisms of action. OBJECTIVES: To elucidate the metabolic pathway of hydroquinone in human melanocytes and to clarify the role of tyrosinase in the development of exogenous ochronosis. METHODS: We conducted an in vitro investigation using human tyrosinase to analyse the metabolism of hydroquinone. The study involved assessing the oxidation of hydroquinone in the presence of L-DOPA and L-cysteine, measuring the production of dopaquinone and its subsequent derivatives, including 2-S-cysteinyl-hydroquinone (Cys-HQ) and hydroquinone-pheomelanin (HQ-PM). RESULTS: Our findings demonstrate that human tyrosinase effectively oxidizes hydroquinone 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 exogenous ochronosis by hydroquinone. Additionally, while high-molecular-weight hydroquinone derivatives may remain within melanosomes, low-molecular-weight metabolites can penetrate the dermis, potentially triggering the polymerization of ochronotic particles similar to those seen in exogenous ochronosis. CONCLUSIONS: Tyrosinase plays a significant role in hydroquinone-induced exogenous ochronosis, suggesting that hydroquinone acts as a 'pseudo' substrate for this enzyme. The findings highlight the importance of using tyrosinase inhibitors to reduce the risk of exogenous ochronosis, while cautioning against other melanogenesis inhibitors that may have similar side effects.