Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine.
Ibogaine is a psychoactive alkaloid that possesses potential as an agent to treat opiate and cocaine addiction. The primary metabolite arises via O-demethylation at the 12-position to yield 12-hydroxyibogamine. In this report, evidence is presented that the O-demethylation of ibogaine observed in human hepatic microsomes is catalyzed primarily by the polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme kinetic examination of ibogaine O-demethylase activity in pooled human liver microsomes suggested that two (or more) enzymes are involved in this reaction: one with a low KMapp (1.1 microM) and the other with a high KMapp (>200 microM). The low KMapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (mean KMapp = 0.55 +/- 0.09 microM and 310 +/- 10 microM for low and high KM activities, respectively). However, a fourth human microsome sample that appeared to be a phenotypic CYP2D6 poor metabolizer possessed only the high KMapp activity. In hepatic microsomes from a panel of human donors, the low KMapp ibogaine O-demethylase activity correlated with CYP2D6-catalyzed bufuralol 1'-hydroxylase activity but not with other P450 isoform-specific activities. Quinidine, a CYP2D6-specific inhibitor, inhibited ibogaine O-demethylase (IC50 = 0.2 microM), whereas other P450 isoform-specific inhibitors did not inhibit this activity. Also, of a battery of recombinant heterologously expressed human P450 isoforms, only rCYP2D6 possessed significant ibogaine O-demethylase activity. Thus, it is concluded that ibogaine O-demethylase is catalyzed by CYP2D6 and that this isoform is the predominant enzyme of ibogaine O-demethylation in humans. The potential pharmacological implications of these findings are discussed.
Department of Drug Metabolism, Central Research Division, Pfizer, Inc., Groton, CT 06340, USA.
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D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006213:Hallucinogens / Q000378:metabolism*; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D007527:Isoenzymes; D007050:Ibogaine; C094385:noribogaine; D019389:Cytochrome P-450 CYP2D6