Document Detail


Bioactivation of benzylamine to reactive intermediates in rodents: formation of glutathione, glutamate, and peptide conjugates.
MedLine Citation:
PMID:  12230413     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The in vivo and in vitro disposition of benzylamine was investigated in rats. Benzylamine was metabolized to only a small extent by rat liver subcellular fractions. In contrast, it was extensively metabolized in vivo in rats. In vivo studies performed with stable isotope-labeled benzylamine enabled rapid mass spectrometric identification of metabolites present in rat bile and urine. The major metabolite of benzylamine was the hippuric acid formed by glycine conjugation of benzoic acid. LC/MS analysis of bile and urine obtained from rats dosed with 1:1 equimolar mixture of either d(0):d(7)- or d(0):d(2)-benzylamine showed the presence of several glutathione adducts in addition to the hippuric acid metabolite. The presence of various glutathione adducts indicated that benzylamine was metabolized to a number of reactive intermediates. Various metabolic pathways, including those independent of P450, were found to produce these intermediates. A previously undocumented pathway included the formation of a new carbon-nitrogen bond that led to a potentially reactive intermediate, Ar-CH(2)-NH(CO)-X, capable of interacting with various nucleophiles. The origin of this reactive intermediate is postulated to occur via the formation of either a formamide or carbamic acid metabolites. Metabolites which were produced by the reaction of this intermediate, Ar-CH(2)-NH(CO)-X with nucleophiles included S-[benzylcarbamoyl] glutathione, N-acetyl-S-[benzylcarbamoyl]cysteine, S-[benzylcarbamoyl] cysteinylglycine, S-[benzylcarbamoyl] cysteinylglutamate, N-[benzylcarbamoyl] glutamate, and an oxidized glutathione adduct. Bioactivation of amines via this pathway has not been previously described. The oxidative deamination of benzylamine yielding the benzaldehyde was demonstrated to be a precursor to the hippuric acid metabolite and S-benzyl-L-glutathione. The formation of the S-benzyl-L-glutathione conjugate showed that a net displacement of amine from benzylamine had taken place with a subsequent addition of glutathione at the benzylic position. In addition to these novel pathways, a number of other glutathione-derived adducts formed as a result of epoxide formation was characterized. It was demonstrated that benzylamine was converted by rat P450 2A1 and 2E1 to benzamide that was rapidly metabolized to an epoxide. Mechanisms are proposed for the formation of various GSH adducts of benzylamine.
Authors:
Abdul E Mutlib; Patricia Dickenson; Shiang-Yuan Chen; Robert J Espina; J Scott Daniels; Liang-Shang Gan
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  15     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2002 Sep 
Date Detail:
Created Date:  2002-09-16     Completed Date:  2003-04-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1190-207     Citation Subset:  IM    
Affiliation:
Drug Metabolism and Pharmacokinetics Section, Bristol-Myers Squibb Pharma Company, Wilmington, Delaware 19880, USA. abdul.mutlib@pfizer.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Benzylamines / pharmacokinetics*
Bile / metabolism
Biotransformation
Chromatography, Liquid
Cytochrome P-450 Enzyme System / classification,  metabolism
Glutamates / biosynthesis*,  chemistry,  urine
Glutathione / analogs & derivatives,  biosynthesis*,  chemistry,  urine
Male
Mass Spectrometry
Microsomes, Liver / metabolism
Nuclear Magnetic Resonance, Biomolecular / methods
Oxidation-Reduction
Oximes / analysis
Rats
Rats, Sprague-Dawley
Subcellular Fractions / metabolism
Chemical
Reg. No./Substance:
0/Benzylamines; 0/Glutamates; 0/Oximes; 100-46-9/benzylamine; 70-18-8/Glutathione; 9035-51-2/Cytochrome P-450 Enzyme System

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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