Metabolism of 2-substituted quinolines with antileishmanial activity studied in vitro with liver microsomes, hepatocytes and recombinantly expressed enzymes analyzed by LC/MS.
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.
Desrivot
Julie
J
Centre d'Etudes Pharmaceutiques, Laboratoire de Pharmacognosie, BioCIS UMR 8076, Université Paris-Sud 11, 5 rue J-B Clément, 92290 Châtenay Malabry, France.
Edlund
Per-Olof
PO
Svensson
Richard
R
Baranczewski
Pawel
P
Fournet
Alain
A
Figadère
Bruno
B
Herrenknecht
Christine
C
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004355:Drug Stability; D020719:Glucuronides / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D007891:Leishmania / Q000187:drug effects*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D020719:Glucuronides; D011804:Quinolines; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1; D005978:Glutathione