Stereoselective N-oxygenation of zimeldine and homozimeldine by the flavin-containing monooxygenase.
The metabolism of (Z)- and (E)-zimeldine and (Z)- and (E)-homozimeldine in hepatic rat and hog microsomes is described. The major metabolite observed in all cases examined was the tertiary amine N-oxide and it was formed at a rate 7-20 times that of norzimeldine or homonorzimeldine. N-Oxygenation requires NADPH and is stimulated by n-octylamine. Thiobenzamide and methimazole significantly inhibit N-oxide formation whereas heat pretreatment of microsomes completely abolishes N-oxide formation, strongly suggesting that zimeldine N-oxygenation if solely dependent on the flavin-containing monooxygenase. Hog liver microsomes N-oxygenate the Z-allylic and homoallylic tertiary amines in marked preference to the E-isomers, whereas rat liver microsomes N-oxygenate E-isomers to a greater extent than Z-isomers. Thus, opposite stereoselectivity for zimeldine N-oxygenation occurs in rat liver and hog liver microsomes.
D000818:Animals; D001711:Biotransformation; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010087:Oxides / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism; D013552:Swine; D015031:Zimeldine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics
D010087:Oxides; C057480:homozimelidine; D015031:Zimeldine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)