Document Detail

Metabolism of 2-substituted quinolines with antileishmanial activity studied in vitro with liver microsomes, hepatocytes and recombinantly expressed enzymes analyzed by LC/MS.
MedLine Citation:
PMID:  17434249     Owner:  NLM     Status:  MEDLINE    
Liver microsome and hepatocyte-mediated biotransformation of three oral antileishmanial 2-substituted quinolines were investigated. One quinoline contains an n-propyl group (1) and the other a propenyl chain functionalized at the gamma position either by a nitrile (2) or an alcohol (3). The different isoforms of rat cytochrome P450 responsible for biotransformation of 1 were also investigated. Compounds 2 and 3 mainly reacted with glutathione, preventing further metabolism. Compound 3 however, the reaction being reversible, could be released from glutathione and take alternative reaction pathways. Microsomal incubations of 1 mainly led to hydroxylation of the side chain, involving many cytochromes, predominantly CYP2B1, CYP2A6 and CYP1A1 (at more than 80%). In contrary, minor metabolites hydroxylated on the quinoline ring involved a few cytochromes. The hydroxylated products of 1 were conjugated with glucuronic acid in rat hepatocyte incubations.
Julie Desrivot; Per-Olof Edlund; Richard Svensson; Pawel Baranczewski; Alain Fournet; Bruno Figadère; Christine Herrenknecht
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-03-12
Journal Detail:
Title:  Toxicology     Volume:  235     ISSN:  0300-483X     ISO Abbreviation:  Toxicology     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-05-07     Completed Date:  2007-06-22     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  27-38     Citation Subset:  IM    
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MeSH Terms
Aryl Hydrocarbon Hydroxylases / metabolism
Chromatography, High Pressure Liquid*
Cytochrome P-450 CYP1A1 / metabolism
Cytochrome P-450 CYP2B1 / metabolism
Cytochrome P-450 Enzyme System / genetics,  metabolism*
Drug Stability
Glucuronides / metabolism
Glutathione / metabolism
Hepatocytes / enzymology,  metabolism*
Leishmania / drug effects*
Mass Spectrometry*
Microsomes, Liver / enzymology,  metabolism*
Mixed Function Oxygenases / metabolism
Molecular Structure
Quinolines / chemistry,  metabolism*,  pharmacology
Rats, Sprague-Dawley
Recombinant Proteins / metabolism
Trypanocidal Agents / chemistry,  metabolism*,  pharmacology
Reg. No./Substance:
0/Glucuronides; 0/Quinolines; 0/Recombinant Proteins; 0/Trypanocidal Agents; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.13.-/coumarin 7-hydroxylase; EC Hydrocarbon Hydroxylases; EC P-450 CYP1A1; EC P-450 CYP2B1; GAN16C9B8O/Glutathione

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

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