Dihydro-1,4-benzothiazine-6,7-dione, the ultimate toxic metabolite of 4- S-Cysteaminylphenol and 4-S-Cysteaminylcatechol

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Abstract

4-S-Cysteaminylphenol (4-S-CAP) and the corresponding catechol 4-S- cysteaminylcatechol (4-SCAC) have been evaluated for melanocytotoxicity. It was shown recently that tyrosinase oxidation of these substrates produces a violet pigment, dihydro-1,4-benzothiazine-6,7-dione (BQ). In this study we examined whether BQ is the ultimate toxic metabolite produced in melanoma cells from 4-S-CAP/4-S-CAC. Biochemical experiments showed that (1) BQ was formed by autoxidation of 4-S-CAC as well as by tyrosinase oxidation of 4-S- CAP/4-S-CAC, (2) BQ reacted rapidly with thiols such as reduced glutathione (GSH), and (3) BQ inhibited the activity of alcohol dehydrogenase, an SH enzyme. In vitro experiments showed that (1) the cytotoxicity of 4-S-CAC was mostly prevented by catalase and superoxide dismutase, (2) BQ was highly cytotoxic to B16 melanoma cells (IC50 being 3.9 μM as compared with 507 μM for 4-S-CAP), (3) BQ was metabolized rapidly to a GSH adduct in melanoma cells, and (4) the same GSH adduct was also formed upon incubation of melanoma cells with 4-S-CAP, the reaction being tyrosinase dependent. In vivo experiments showed that intratumoral administration of BQ (0.5 μmol) inhibited the subcutaneous growth of B16 melanoma nearly as effectively as 4- S-CAP/4-S-CAC (20 μmol). These results indicate that BQ is the ultimate toxic metabolite produced by tyrosinase oxidation of 4-S-CAP/4-S-CAC. BQ deprives melanoma cells of GSH and may inactivate SH enzymes essential for DNA synthesis and cell proliferation by covalent binding through their cysteine residues, thereby exerting melanocytotoxicity. Cytotoxicity of 4-S- CAC depends mostly on autoxidation producing BQ and active oxygens.

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Hasegawa, K., Ito, S., Inoue, S., Wakamatsu, K., Ozeki, H., & Ishiguro, I. (1997). Dihydro-1,4-benzothiazine-6,7-dione, the ultimate toxic metabolite of 4- S-Cysteaminylphenol and 4-S-Cysteaminylcatechol. Biochemical Pharmacology, 53(10), 1435–1444. https://doi.org/10.1016/S0006-2952(97)00075-0

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