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...
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2025-01-01
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| author | Tomoko Nishimaki-Mogami Shosuke Ito Kazumasa Wakamatsu Takumi Akiyama Norimasa Tamehiro Norihito Shibata |
| author_facet | Tomoko Nishimaki-Mogami Shosuke Ito Kazumasa Wakamatsu Takumi Akiyama Norimasa Tamehiro Norihito Shibata |
| author_sort | Tomoko Nishimaki-Mogami |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1402e4214f4d42bab2b11e08401293b8 |
| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-1402e4214f4d42bab2b11e08401293b82025-01-24T13:25:14ZengMDPI AGBiomolecules2218-273X2025-01-0115111410.3390/biom15010114A 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 CellsTomoko Nishimaki-Mogami0Shosuke Ito1Kazumasa Wakamatsu2Takumi Akiyama3Norimasa Tamehiro4Norihito Shibata5Division of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, JapanInstitute for Melanin Chemistry, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, JapanInstitute for Melanin Chemistry, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, JapanDivision of Environmental Chemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, JapanDivision of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, JapanDivision of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, JapanChemical 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.https://www.mdpi.com/2218-273X/15/1/114chemical leukoderma<i>o</i>-quinonetyrosinaseNrf2Slc7a11Nqo1 |
| spellingShingle | Tomoko Nishimaki-Mogami Shosuke Ito Kazumasa Wakamatsu Takumi Akiyama Norimasa Tamehiro Norihito Shibata 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 Biomolecules chemical leukoderma <i>o</i>-quinone tyrosinase Nrf2 Slc7a11 Nqo1 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | chemical leukoderma <i>o</i>-quinone tyrosinase Nrf2 Slc7a11 Nqo1 |
| url | https://www.mdpi.com/2218-273X/15/1/114 |
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