A Cell-Based Evaluation of the Tyrosinase-Mediated Metabolic Activation of Leukoderma-Inducing Phenols, II: The Depletion of <i>Nrf2</i> Augments the Cytotoxic Effect Evoked by Tyrosinase in Melanogenic Cells
Chemical leukoderma is a disorder induced by chemicals such as rhododendrol and monobenzone. These compounds possess a <i>p</i>-substituted phenol moiety and undergo oxidation into highly reactive and toxic <i>o</i>-quinone metabolites by tyrosinase. This metabolic activation...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/1/114 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Chemical leukoderma is a disorder induced by chemicals such as rhododendrol and monobenzone. These compounds possess a <i>p</i>-substituted phenol moiety and undergo oxidation into highly reactive and toxic <i>o</i>-quinone metabolites by tyrosinase. This metabolic activation plays a critical role in the development of leukoderma through the production of damage to melanocytes and immunological responses. This study aimed to develop a simple method for assessing the metabolic activation of leukoderma-inducing phenols without analyzing the metabolite. Although B16BL6 melanoma cells showed insufficient sensitivity to the cytotoxicity assay, the siRNA-mediated knockdown of the transcription factor NRF2 (NFE2L2) repressed the expression of cytoprotective factors, thereby augmenting the cytotoxicity of all six leukoderma-inducing phenols tested in a tyrosinase-dependent manner, indicating enhanced sensitivity to <i>o</i>-quinone metabolites. Additionally, the knockdown of the NRF2-target <i>Slc7a11</i> elevated the cytotoxicity of three out of the six compounds, indicating the involvement of cystine transport in cellular protection. In contrast, the knockdown or inhibition of the NRF2-target <i>Nqo1</i> had minimal effects. The same response was induced upon <i>Nrf2</i> and <i>Slc7a11</i> knockdown in B16-4A5 cells, albeit with low sensitivity owing to low tyrosinase expression. We conclude that the analysis of tyrosinase-dependent cytotoxicity in <i>Nrf2</i>-depleted B16BL6 cells may serve as a useful strategy for evaluating the metabolic activation of chemicals. |
|---|---|
| ISSN: | 2218-273X |