| Metabolism of chlorambucil by rat liver microsomal glutathione S-transferase. | |
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MedLine Citation:
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PMID: 15356922 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Clinical efficacy of alkylating anticancer drugs, such as chlorambucil (4-[p-[bis [2-chloroethyl] amino] phenyl]-butanoic acid; CHB), is often limited by the emergence of drug resistant tumor cells. Increased glutathione (gamma-glutamylcysteinylglycine; GSH) conjugation (inactivation) of alkylating anticancer drugs due to overexpression of cytosolic glutathione S-transferase (GST) is believed to be an important mechanism in tumor cell resistance to alkylating agents. However, the potential involvement of microsomal GST in the establishment of acquired drug resistance (ADR) to CHB remains uncertain. In our experiments, a combination of lipid chromatography/electrospray ionization mass spectrometry (LC/ESI/MS) was employed for structural characterization of the resulting conjugates between CHB and GSH. The spontaneous reaction of 1mM CHB with 5 mM GSH at 37 degrees C in aqueous phosphate buffer for 1 h gave primarily the monoglutathionyl derivative, 4-[p-[N-2-chloroethyl, N-2-S-glutathionylethyl] amino]phenyl]-butanoic acid (CHBSG) and the diglutathionyl derivative, 4-[p-[2-S-glutathionylethyl] amino]phenyl]-butanoic acid (CHBSG2) with small amounts of the hydroxy-derivative, 4-[p-[N-2-S-glutathionylethyl, N-2-hydroxyethyl] amino]phenyl]-butanoic acid (CHBSGOH), 4-[p-[bis[2-hydroxyethyl] amino]phenyl]-butanoic acid (CHBOH2), 4-[p-[N-2-chloroethyl, N-2-S-hydroxyethyl]amino]phenyl]-butanoic acid (CHBOH). We demonstrated that rat liver microsomal GST presented a strong catalytic effect on these reactions as determined by the increase of CHBSG2, CHBSGOH and CHBSG and the decrease of CHB. We showed that microsomal GST was activated by CHB in a concentration and time dependent manner. Microsomal GST which was stimulated approximately two-fold with CHB had a stronger catalytic effect. Thus, microsomal GST may play a potential role in the metabolism of CHB in biological membranes, and in the development of ADR. |
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Authors:
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Jie Zhang; Zhiwei Ye; Yijia Lou |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Chemico-biological interactions Volume: 149 ISSN: 0009-2797 ISO Abbreviation: Chem. Biol. Interact. Publication Date: 2004 Aug |
Date Detail:
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Created Date: 2004-09-09 Completed Date: 2004-09-29 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0227276 Medline TA: Chem Biol Interact Country: Ireland |
Other Details:
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Languages: eng Pagination: 61-7 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents, Alkylating / metabolism, pharmacology* Catalysis / drug effects Chlorambucil / metabolism, pharmacology* Chromatography, High Pressure Liquid Dose-Response Relationship, Drug Drug Resistance, Neoplasm / drug effects, physiology Enzyme Inhibitors / pharmacology Ethylmaleimide / pharmacology Glutathione Transferase / metabolism* Male Microsomes, Liver / drug effects*, enzymology* Rats Rats, Sprague-Dawley Spectrometry, Mass, Electrospray Ionization |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Alkylating; 0/Enzyme Inhibitors; 128-53-0/Ethylmaleimide; 305-03-3/Chlorambucil; EC 2.5.1.18/Glutathione Transferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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