ATYPICAL METABOLISM OF DEPRENYL AND ITS ENANTIOMER, (S)-(-N,ALPHA-DIMETHYL-N-PROPYNYLPHENETHYLAMINE BY CYTOCHROME-P450 2D6())

Citation
Jm. Grace et al., ATYPICAL METABOLISM OF DEPRENYL AND ITS ENANTIOMER, (S)-(-N,ALPHA-DIMETHYL-N-PROPYNYLPHENETHYLAMINE BY CYTOCHROME-P450 2D6()), Chemical research in toxicology, 7(3), 1994, pp. 286-290
Citations number
35
Categorie Soggetti
Toxicology,Chemistry
ISSN journal
0893228X
Volume
7
Issue
3
Year of publication
1994
Pages
286 - 290
Database
ISI
SICI code
0893-228X(1994)7:3<286:AMODAI>2.0.ZU;2-X
Abstract
Debrisoquine 4-hydroxylase is a unique cytochrome P450 that effects ox idation of protonated substrates at sites distal from the basic nitrog en. A basic tenet of the several models that have been proposed for th e active site of P450 2D6 is that oxidation occurs at distances of sim ilar to 5 or similar to 7 A from the protonated site. In this study, t he metabolism of both stereoisomers of deprenyl, a therapeutically val uable monoamine oxidase B inhibitor, was shown to produce N-demethylat ion and N-depropargylation of the sole basic nitrogen in the molecule by recombinant cytochrome P450 2D6. N-Demethylation of L-(-)-deprenyl leading to nordeprenyl was favored by approximate to 13:1 over N-depro pargylation which produced methamphetamine. The K-m and K-cat values f or formation of methamphetamine, the minor metabolite, were 56 +/- 5 m u M and 0.63 +/- 0.063 nmol of methamphetamine min(-1) (nmol of P450)( -1), respectively; the K-cat for nordeprenyl formation was approximate to 8.2 nmol of nordeprenyl min(-1) (nmol of P450)(-1). Although these pathways would be the anticipated processes for monoamine oxidases an d most cytochrome P450s, this mode of biotransformation is not predict ed by current active site models and represents a novel pathway for P4 50 2D6. Statistical analysis indicates that the therapeutically import ant L-(-)-isomer was preferentially metabolized [k(cat)/K-m (-)/(+) ra tio 2.66]. Competitive inhibition of deprenyl metabolism by both quini dine and quinine with an approximate 10(3) differential confirms that this metabolic pathway is P450 2D6 mediated. We hypothesize that L-(-) -deprenyl free base, in equilibrium with the ammonium-carboxylate salt bridge within the active site, is released and subjected to rapid ele ctron-transfer oxidation by the active oxygen species. The last step o f this sequence would be facilitated by the low basicity and low redox potential of tertiary amines. Thus, deprenyl may represent a novel cl ass of P450 2D6 substrates that undergo an ''atypical'' 2DG-mediated N -dealkylation process as a consequence of structural features inhibiti ng the prototypic process and electronic features facilitating N-oxida tion reactions.