Enantioselective N-oxygenation of chlorpheniramine by the flavin-containing monooxygenase from hog liver.
1. The metabolism of racemic, (D)- and (L)-chlorpheniramine, a widely used antihistamine, was studied in microsomes and with highly purified flavin-containing monooxygenase from hog liver. 2. Although some N-demethylation was observed, the major metabolite of chlorpheniramine in hog liver microsomes was the aliphatic nitrogen N-oxide. Chlorpheniramine was extensively N-oxygenated by the highly purified flavin-containing monooxygenase from hog liver. 3. N-Oxygenation of chlorpheniramine in both microsomes and highly purified flavin-containing monooxygenase from hog liver was enantioselective. The Km for (D)-chlorpheniramine N-oxygenation was markedly lower than that for (L)-chlorpheniramine. 4. Molecular modelling studies were performed to investigate the nature of the substrate binding region.
Cashman
J R
JR
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446.
Celestial
J R
JR
Leach
A R
AR
D000818:Animals; D001665:Binding Sites; D002744:Chlorpheniramine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D008658:Inactivation, Metabolic; D008862:Microsomes, Liver / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D010105:Oxygenases / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013552:Swine
C076662:chlorpheniramine N-oxide; D002744:Chlorpheniramine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)