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Novel insights into conjugation of antitumor-active unsymmetrical bisacridine C-2028 with glutathione: characteristics of non-enzymatic and glutathione S-transferase-mediated reactions
Abstract
Unsymmetrical bisacridines (UAs) are a novel potent class of antitumor-active therapeutics. A significant route of phase II drug metabolism is conjugation with glutathione (GSH), which can be non-enzymatic and/or catalyzed by GSH-dependent enzymes. The aim of this work was to investigate the GSH-mediated metabolic pathway of a representative UA, C 2028. GSH supplemented incubations of C-2028 with rat, but not with human, liver cytosol led to the formation of a single GSH-related metabolite. Interestingly, it was also revealed with rat liver microsomes. Its formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450 inhibitor 1-aminobenzotriazole. Therefore, the direct conjugation pathway occurred without the prior P450-catalyzed bioactivation of the substrate. In turn, incubations of C-2028 and GSH with human recombinant GSTP1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form, respectively. These findings proved the necessary participation of glutathione S-transferase (GST) in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate molecule. Another C-2028-GSH S-conjugate was also formed during non-enzymatic reaction. Both GSH S-conjugates were characterized by combined liquid chromatography/tandem mass spectrometry. Mechanisms for their formation were proposed. The ability of C-2028 to GST mediated and/or direct GSH conjugation is suspected to be clinically important. This may affect the patient’s drug clearance due to GST activity, loss of GSH, or the interactions with GSH conjugated drugs. Moreover, GST mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.
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- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.jpha.2021.03.014
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- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
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Journal of Pharmaceutical Analysis
no. 11,
pages 791 - 798,
ISSN: 2095-1779 - Language:
- English
- Publication year:
- 2021
- Bibliographic description:
- Potęga A., Kosno M., Mazerska Z.: Novel insights into conjugation of antitumor-active unsymmetrical bisacridine C-2028 with glutathione: characteristics of non-enzymatic and glutathione S-transferase-mediated reactions// Journal of Pharmaceutical Analysis -Vol. 11,iss. 6 (2021), s.791-798
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.jpha.2021.03.014
- Verified by:
- Gdańsk University of Technology
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