| Relationship between activation of microsomal glutathione S-transferase and metabolism behavior of chlorambucil. | |
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MedLine Citation:
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PMID: 14527828 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Chlorambucil (4-[p-[bis [2-chloroethyl] amino] phenyl]-butanoic acid; CMB) is a bifunctional alkylating agent that exhibits acquired drug resistance upon repeated dosing in human. This compound reacts with glutathione (gamma-glutamylcysteinylglycine, GSH) both non-enzymatically and enzymatically in the presence of glutathione S-transferases (GSTs) to produce several GSH conjugates. The formation of GSH conjugates of this class of alkylating agents may play a role in the development of acquired drug resistance. In this study, the effect of CMB on microsomal GST (mGST) activity and the catalytic effect of mGST on the formation of GSH conjugates of CMB were investigated. mGST was activated by CMB in a concentration- and time-dependent manner. NEM failed to reactivate the CMB pretreated mGST. This suggests that mGST could be activated by CMB, possibly via reacting with the single cysteine (Cys49) in mGST. The resulting conjugates of GSH and CMB were characterized by a combination of lipid chromatography/electrospray ionization mass spectrometry (LC/ESI/MS). mGST presented a strong catalytic effect on the reaction as determined by the increase of the diglutathionyl derivative, 4-[p-[bis[2-S-glutathionylethyl] amino]phenyl]-butanoic acid (CMBSG2), monoglutathionyl derivatives, 4-[p-[N-2-chloroethyl, N-2-S-glutathionylethyl] amino]phenyl]-butanoic acid (CMBSG) and 4-[p-[N-2-S-glutathionylethyl, N-2-hydroxyethyl] amino]phenyl]-butanoic acid (CMBSGOH) and the decrease of CMB. mGST which was stimulated approximately 2.5-fold with CMB had a stronger catalytic effect. These results suggest the potential role of the activation of mGST in the CMB inactivation and in the development of acquired drug resistance. |
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Authors:
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Jie Zhang; Yi-Jia Lou |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Pharmacological research : the official journal of the Italian Pharmacological Society Volume: 48 ISSN: 1043-6618 ISO Abbreviation: Pharmacol. Res. Publication Date: 2003 Dec |
Date Detail:
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Created Date: 2003-10-06 Completed Date: 2004-08-12 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8907422 Medline TA: Pharmacol Res Country: England |
Other Details:
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Languages: eng Pagination: 623-30 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310031, PR China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Catalysis / drug effects Chlorambucil / chemistry, pharmacology* Dose-Response Relationship, Drug Enzyme Activation / drug effects Glutathione / chemistry Glutathione Transferase / isolation & purification, metabolism* Male Microsomes, Liver / enzymology* Rats Rats, Sprague-Dawley Spectrometry, Mass, Electrospray Ionization / methods Time Factors |
| Chemical | |
Reg. No./Substance:
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305-03-3/Chlorambucil; 70-18-8/Glutathione; EC 2.5.1.18/Glutathione Transferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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