{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:03:16Z","timestamp":1790348596281,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Sesamol (3,4-methylenedioxyphenol) is a unique natural phenolic compound derived from sesame seeds that is characterized by its concurrent phenolic and methylenedioxy moieties. The purpose of this study was to investigate the tyrosinase-mediated metabolic activation of sesamol to determine whether a cytotoxic quinone intermediate is produced, mirroring the mechanism established for p-substituted phenols such as resveratrol. Although sesamol is recognized as a potent tyrosinase inhibitor, we demonstrate that in the presence of catalytic amounts of L-DOPA, it serves as an efficient substrate for tyrosinase-mediated bioactivation. The resulting metabolite, sesamol-5,6-quinone, was identified via reduction with NaBH4 or ascorbic acid to its corresponding catechol, followed by isolation through acetylation to stabilize the transient species. The reactive nature of sesamol-5,6-quinone was confirmed through the formation of covalent adducts with N-acetylcysteine. In metabolic experiments using human tyrosinase-expressing 293T cells, we identified the reactive metabolite, sesamol-5,6-quinone, through the formation of intracellular thiol adducts released into the medium. While sesamol is systemically protective, it induced a marked tyrosinase-dependent cytotoxicity in B16BL6 melanoma cells, which was significantly suppressed by tyrosinase knockdown. Crucially, sesamol oligomers exhibited potent pro-oxidant activity, generating hydrogen peroxide and depleting reduced glutathione through its oxidation to GSSG. These findings suggest that tyrosinase-mediated conversion transforms sesamol into a highly reactive pro-oxidant, which induces substantial cytotoxicity in melanin-producing cells via protein arylation and profound redox imbalance.<\/jats:p>","DOI":"10.3390\/ijms27198597","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:36:34Z","timestamp":1790346994000},"page":"8597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Dual Nature of Sesamol: Tyrosinase-Dependent Bioactivation from an Inhibitor to a Cytotoxic Pro-Oxidant"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5646-9620","authenticated-orcid":false,"given":"Hitomi","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Medical Technology, School of Health Sciences, Gifu University of Medical Science, 795-1 Nagamine, Ichihiraga, Seki 501-3892, Gifu, Japan"},{"name":"Institute for Melanin Chemistry, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0194-2377","authenticated-orcid":false,"given":"Tomoko","family":"Nishimaki-Mogami","sequence":"additional","affiliation":[{"name":"Division of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.biochi.2010.11.014","article-title":"Interaction of sesamol (3,4-methylenedioxyphenol) with tyrosinase and its effect on melanin synthesis","volume":"93","author":"Kumar","year":"2011","journal-title":"Biochimie"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1021\/jf0303621","article-title":"Free radical scavenging behavior of antioxidant compounds of sesame (Sesamum indicum L.) in DPPH system","volume":"52","author":"Suja","year":"2004","journal-title":"J. Agric. Food Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1080\/87559129509541043","article-title":"The chemistry and physiological functions of sesame","volume":"11","author":"Namiki","year":"1995","journal-title":"Food Rev. Intl."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nair, A.B., Dalal, P., Kadian, V., Kumar, S., Garg, M., Rao, R., Almuqbil, R.A., Alnaim, A.S., Aldhubiab, B., and Alqattan, F. (2023). Formulation strategies for enhancing pharmaceutical and nutraceutical potential for sesamol: A natural phenolic bioactive. Plants, 12.","DOI":"10.3390\/plants12051168"},{"key":"ref_5","first-page":"1","article-title":"An insight into sesamol: Pharmacological activities, and future research prospects","volume":"6","author":"Khatoon","year":"2022","journal-title":"Int. J. Sci. Res. Eng. Manag."},{"key":"ref_6","first-page":"69","article-title":"Antioxidant, antimelanogenic, and skin-protective effect of sesamol","volume":"65","author":"Srisayam","year":"2014","journal-title":"J. Cosmet. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"You, Y.-J., Wu, P.-Y., Liu, Y.-J., Hou, C.-W., Wu, C.-S., Wen, K.-C., Lin, C.-Y., and Chiang, H.-M. (2019). Sesamol inhibited ultraviolet radiation-induced hyperpigmentation and damage in C57BL\/6 mouse skin. Antioxidants, 8.","DOI":"10.3390\/antiox8070207"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.5530\/ijper.53.2s.46","article-title":"Sesamol and health\u2014A comprehensive review","volume":"53","author":"Shah","year":"2019","journal-title":"Indian J. Pharm. Educ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1002\/ptr.6428","article-title":"A systematic review on antioxidant and anti-inflammatory activity of Sesame (Sesamum indicum L.) oil and further confirmation of antiinflammatory activity by chemical profiling and molecular docking","volume":"33","author":"Afroz","year":"2019","journal-title":"Phytother. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9566","DOI":"10.1021\/acsomega.0c00898","article-title":"Computationally designed sesamol derivatives proposed as potent antioxidants","volume":"5","author":"Galano","year":"2020","journal-title":"ACS Omega"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Buravlev, E.V., Shevchenko, O.G., and Suponitsky, K.Y. (2021). Synthesis and antioxidant capacity of some derivatives of sesamol at the C-6 position. Chem. Biodivers., 18.","DOI":"10.1002\/cbdv.202100221"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Smarzewska, S., Guziejewski, D., Ullah, N., and Koszelska, K. (2023). Electrochemical evaluation of free radical scavenging activity of sesamol. J. Electrochem. Soc., 170.","DOI":"10.1149\/1945-7111\/acd1b9"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s00403-010-1072-1","article-title":"Sesamol inhibits UVB-induced ROS generation and subsequent oxidative damage in cultured human skin dermal fibroblasts","volume":"302","author":"Ramachandran","year":"2010","journal-title":"Arch. Dermatol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1111\/1541-4337.12566","article-title":"Natural phenolic antioxidants electrochemistry: Towards a new food science methodology","volume":"19","author":"Enache","year":"2020","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1080\/1028415X.2025.2457051","article-title":"The prospective therapeutic benefits of sesamol: Neuroprotection in neurological diseases","volume":"28","author":"Guo","year":"2025","journal-title":"Nutr. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.apjtb.2017.09.013","article-title":"Inhibition of two stages of melanin synthesis by sesamol, sesamin and sesamolin","volume":"7","author":"Srisayam","year":"2017","journal-title":"Asian Pac. J. Trop. Biomed."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Srisongkram, T., and Weerapreeyakul, N. (2022). Route of intracellular uptake and cytotoxicity of sesamol, sesamin, and sesamolin in human melanoma SK-MEL-2 cells. Biomed. Pharmacother., 146.","DOI":"10.1016\/j.biopha.2021.112528"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/exd.12765","article-title":"Sesamol decreases melanin biosynthesis in melanocyte cells and zebrafish: Possible involvement of MITF via the intracellular cAMP and p38\/JNK signalling pathways","volume":"24","author":"Baek","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wu, P.-Y., You, Y.-J., Liu, Y.-J., Hou, C.-W., Wu, C.-S., Wen, K.-C., Lin, C.-Y., and Chiang, H.-M. (2018). Sesamol inhibited melanogenesis by regulating melanin-related signal transduction in B16F10 cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041108"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/pcmr.12556","article-title":"The potent pro-oxidant activity of rhododendrol-eumelanin induces cysteine depletion in B16 melanoma cells","volume":"30","author":"Ito","year":"2017","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tanaka, H., Nishimaki-Mogami, T., Tamehiro, N., Shibata, N., Mandai, H., Ito, S., and Wakamatsu, K. (2024). Pterostilbene, a dimethyl derivative of resveratrol, exerts cytotoxic effects on melanin-producing cells through metabolic activation by tyrosinase. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25189990"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.bmc.2011.11.030","article-title":"Resveratrol as a kcat type inhibitor for tyrosinase: Potentiated melanogenesis inhibitor","volume":"20","author":"Satooka","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tanaka, H., Ito, S., Ojika, M., Nishimaki-Mogami, T., Kondo, K., and Wakamatsu, K. (2021). The oxidation of equol by tyrosinase produces a unique di-ortho-quinone: Possible implications for melanocyte toxicity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179145"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nordlund, J.J., Boissy, R.E., Hearing, V.J., King, R.A., Oetting, W.S., and Ortonne, J.-P. (2006). Enzymology of melanin formation. The Pigmentary System: Physiology and Pathophysiology, Wiley Blackwell. [2nd ed.].","DOI":"10.1002\/9780470987100"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/0041-008X(92)90273-U","article-title":"Quinone chemistry and toxicity","volume":"112","author":"Monks","year":"1992","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1021\/tx900018q","article-title":"A Reactive ortho-quinone generated by tyrosinase-catalyzed oxidation of the skin depigmenting agent monobenzone: Self-coupling and thiol-conjugation reactions and possible implications for melanocyte toxicity","volume":"22","author":"Manini","year":"2009","journal-title":"Chem. Res. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Eriksen, T.H. (2016). Overheating: An Anthropology of Accelerated Change, Pluto Press. [1st ed.].","DOI":"10.2307\/j.ctt1cc2mxj"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1620\/tjem.212.341","article-title":"The mechanism of suicide-inactivation of tyrosinase: A substrate structure investigation","volume":"212","author":"Land","year":"2007","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1038\/jid.2011.16","article-title":"Skin-depigmenting agent monobenzone induces potent T-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome autophagy","volume":"131","author":"Picavet","year":"2011","journal-title":"J. Investig. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1038\/jid.2012.181","article-title":"Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8","volume":"132","author":"Toosi","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.tiv.2016.02.003","article-title":"Rhododenol and raspberry ketone impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45","volume":"32","author":"Kim","year":"2016","journal-title":"Toxicol. In Vitro"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1021\/acs.chemrestox.7b00006","article-title":"Tyrosinase-catalyzed oxidation of the leukoderma-inducing agent raspberry ketone produces (E)-4-(3-oxo-1-butenyl)-1,2-benzoquinone: Implications for melanocyte toxicity","volume":"30","author":"Ito","year":"2017","journal-title":"Chem. Res. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/pcmr.12808","article-title":"Tyrosinase-catalyzed oxidation of resveratrol produces a highly reactive ortho-quinone: Implications for melanocyte toxicity","volume":"32","author":"Ito","year":"2019","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jdermsci.2022.12.002","article-title":"A cell-based evaluation of human tyrosinase-mediated metabolic activation of leukoderma-inducing phenolic compounds","volume":"108","author":"Ito","year":"2022","journal-title":"J. Dermatol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/0378-4347(87)80197-4","article-title":"Determination of natural thiols by liquid chromatography after derivatization with 3,5-di-tert-butyl-1,2-benzoquinone","volume":"420","author":"Imai","year":"1987","journal-title":"J. Chromatogr."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ito, S., Sugumaran, M., and Wakamatsu, K. (2020). Chemical reactivities of ortho-quinones produced in living organisms: Fate of quinonoid products formed by tyrosinase and phenoloxidase action on phenols and catechols. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176080"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0301-4622(99)00149-0","article-title":"Kinetic study of the oxidation of 3-hydroxyanisole catalysed by tyrosinase","volume":"84","author":"Fenoll","year":"2000","journal-title":"Biophys. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1021\/jf0489769","article-title":"Free radical reactions and antioxidant activities of sesamol:\u2009 Pulse radiolytic and biochemical studies","volume":"53","author":"Joshi","year":"2005","journal-title":"J. Agric. Food Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1039\/C9FO01873E","article-title":"Sesamol: A powerful functional food ingredient from sesame oil for cardioprotection","volume":"11","author":"Jayaraj","year":"2020","journal-title":"Food Funct."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.tox.2004.12.009","article-title":"Radioprotective effect of sesamol on \u03b3-radiation induced DNA damage, lipid peroxidation and antioxidants levels in cultured human lymphocytes","volume":"209","author":"Prasad","year":"2005","journal-title":"Toxicology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1006\/abio.1997.2392","article-title":"A one-step fluorometric method for the continuous measurement of monoamine oxidase activity","volume":"253","author":"Zhou","year":"1997","journal-title":"Anal. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:37:26Z","timestamp":1790347046000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":41,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198597"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198597","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]}}}