The Dual Nature of Sesamol: Tyrosinase-Dependent Bioactivation from an Inhibitor to a Cytotoxic Pro-Oxidant.
- 1Department of Medical Technology, School of Health Sciences, Gifu University of Medical Science, 795-1 Nagamine, Ichihiraga, Seki 501-3892, Gifu, Japan.
- 2Institute for Melanin Chemistry, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Aichi, Japan.
- 3Division of Biochemistry, National Institute of Health Sciences, Kawasaki-ku, Kawasaki 210-9501, Kanagawa, Japan.
Abstract
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.
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BibTeX
@article{tanaka2026dual,
title = {{The Dual Nature of Sesamol: Tyrosinase-Dependent Bioactivation from an Inhibitor to a Cytotoxic Pro-Oxidant.}},
author = {Hitomi Tanaka and Tomoko Nishimaki-Mogami and Shosuke Ito and Kazumasa Wakamatsu},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198597},
url = {https://europepmc.org/article/MED/42883844},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Dual Nature of Sesamol: Tyrosinase-Dependent Bioactivation from an Inhibitor to a Cytotoxic Pro-Oxidant.
AU - Hitomi Tanaka
AU - Tomoko Nishimaki-Mogami
AU - Shosuke Ito
AU - Kazumasa Wakamatsu
PY - 2026
DA - 2026/09/25
JO - International journal of molecular sciences
DO - 10.3390/ijms27198597
UR - https://europepmc.org/article/MED/42883844
AB - 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.
SN - 1422-0067
ER -