Novel insights into conjugation of antitumor-active unsymmetrical bisacridine C-2028 with glutathione:Characteristics of non-enzymatic and glutathione S-transferase-mediated reactions

作     者：Agnieszka Potega Michal Kosno Zofia Mazerska Agnieszka Pot(e)ga;Michat Kosno;Zofia Mazerska

作者机构：Department of Pharmaceutical Technology and BiochemistryFaculty of ChemistryGda nsk University of TechnologyGda
nsk80-233Poland 

出 版 物：《Journal of Pharmaceutical Analysis》 (药物分析学报（英文版）)

年 卷 期：2021年第11卷第6期

页      面：791-798页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：Department of Analytical Chemistry Department of Pharmaceutical Technology and Biochemistry Shim-pol A.M. Borzymowski Company, (LCMS-2020) Politechnika Gdańska, GUT 

主　　题：Antitumor agent Unsymmetrical bisacridine Metabolic detoxification Glutathione S-Conjugate Glutathione S-transferase Non-enzymatic conjugation 

摘      要：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 *** aim of this work was to investigate the GSHmediated metabolic pathway of a representative UA,***-supplemented incubations of C-2028 with rat,but not with human,liver cytosol led to the formation of a single GSH-related ***,it was also revealed with rat liver *** formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450(CYP450) inhibitor ***,the direct conjugation pathway occurred without the prior CYP450-catalyzed bioactivation of the *** turn,incubations of C-2028 and GSH with human recombinant glutathione S-transferase(GST) P1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form,*** findings proved the necessary participation of GST in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate *** C-2028-GSH S-conjugate was also formed during non-enzymatic *** GSH S-conjugates were characterized by combined liquid chromatography/tandem mass *** for their formation were *** ability of C-2028 to GST-mediated and/or direct GSH conjugation is suspected to be clinically *** may affect the patient’s drug clearance due to GST activity,loss of GSH,or the interactions with GSH-conjugated ***,GST-mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.