{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:37:22Z","timestamp":1759970242495,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health, Labour and Welfare","award":["21KC2003"],"award-info":[{"award-number":["21KC2003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Chemical leukoderma is a disorder induced by chemicals such as rhododendrol and monobenzone. These compounds possess a p-substituted phenol moiety and undergo oxidation into highly reactive and toxic o-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 o-quinone metabolites. Additionally, the knockdown of the NRF2-target Slc7a11 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 Nqo1 had minimal effects. The same response was induced upon Nrf2 and Slc7a11 knockdown in B16-4A5 cells, albeit with low sensitivity owing to low tyrosinase expression. We conclude that the analysis of tyrosinase-dependent cytotoxicity in Nrf2-depleted B16BL6 cells may serve as a useful strategy for evaluating the metabolic activation of chemicals.<\/jats:p>","DOI":"10.3390\/biom15010114","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T04:01:52Z","timestamp":1736740912000},"page":"114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Cell-Based Evaluation of the Tyrosinase-Mediated Metabolic Activation of Leukoderma-Inducing Phenols, II: The Depletion of Nrf2 Augments the Cytotoxic Effect Evoked by Tyrosinase in Melanogenic Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0194-2377","authenticated-orcid":false,"given":"Tomoko","family":"Nishimaki-Mogami","sequence":"first","affiliation":[{"name":"Division of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9182-5144","authenticated-orcid":false,"given":"Shosuke","family":"Ito","sequence":"additional","affiliation":[{"name":"Institute for Melanin Chemistry, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-9001","authenticated-orcid":false,"given":"Kazumasa","family":"Wakamatsu","sequence":"additional","affiliation":[{"name":"Institute for Melanin Chemistry, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Akiyama","sequence":"additional","affiliation":[{"name":"Division of Environmental Chemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norimasa","family":"Tamehiro","sequence":"additional","affiliation":[{"name":"Division of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5792-8510","authenticated-orcid":false,"given":"Norihito","family":"Shibata","sequence":"additional","affiliation":[{"name":"Division of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1001\/jama.1939.72800350003010a","article-title":"Occupational leukoderma","volume":"113","author":"Oliver","year":"1939","journal-title":"J. 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