2002
DOI: 10.1074/jbc.m205146200
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Oxidation of Methoxyphenethylamines by Cytochrome P450 2D6

Abstract: Cytochrome P450 (P450) 2D6 is involved in the oxidation of a large fraction (ϳ30%) of drugs used by humans and also catalyzes the O-demethylation of the model substrates 3-and 4-methoxyphenethylamine followed by subsequent ring hydroxylation to dopamine. Burst kinetics were not observed; rate-limiting step(s) must occur prior to product formation. Rates of reduction of ferric P450 2D6 were stimulated by 3-or 4-methoxyphenethylamine or the inhibitor quinidine; reduction is not the most rate-limiting step. The n… Show more

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Cited by 59 publications
(74 citation statements)
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References 73 publications
(83 reference statements)
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“…6) In conclusion, our results demonstrating a relatively slow conversion of tyramine, via dopamine, into morphine are supported by our enzymology studies of CYP2D6 showing a 10-fold lower binding affinity of tyramine to the active site of the enzyme as compared with the 3-OH-analog (8,9 …”
supporting
confidence: 71%
See 1 more Smart Citation
“…6) In conclusion, our results demonstrating a relatively slow conversion of tyramine, via dopamine, into morphine are supported by our enzymology studies of CYP2D6 showing a 10-fold lower binding affinity of tyramine to the active site of the enzyme as compared with the 3-OH-analog (8,9 …”
supporting
confidence: 71%
“…Additionally, the authors demonstrate conversion of radiolabeled codeine to morphine in WBC, although they have not used appropriate CYP2D6 inhibitors. This is not surprising based on in vitro studies demonstrating that CYP2D6 demethylation occurs faster than ring hydroxylation, i.e., rapid conversion of codeine to morphine (8,9). In light of the above, we do not understand why the authors conclude that WBC do not synthesize morphine.…”
mentioning
confidence: 60%
“…Deuterated 7-OMe coumarins were prepared by reaction of 7-OH coumarin with deuterated methyl iodides (Cambridge Isotopes, Cambridge, MA) in the usual manner (29,37,38) The synthesis of 3-OH coumarins was done using the general procedure of Neubauer and Flatow (42), which involves condensation of salicylaldehyde or a 4-substituted salicylaldehyde with hippuric acid (N-benzoylglycine) to form the N-benzoyl enamine, which was hydrolyzed in 10 N NaOH (100°C, 45 min) to give the desired coumarin. Enzymes-P450 2A6 was expressed from a plasmid (originally obtained from P. Soucek, National Institute of Public Health, Prague) in Escherichia coli, except that a His 5 tag was attached to the C terminus (24,46).…”
Section: Methodsmentioning
confidence: 99%
“…Moreover, the observed kinetic isotope effects can very considerably with different P450s and different reactions even though all are of low efficiency (31,34). The variability of observed kinetic isotope effects in various P450 reactions (28,29,31,34,94) is further extended in further work with human P450s 2E1 and 3A4 (95,96). Thus, the branched nature of the P450 reactions can contribute to the higher expression of kinetic isotope effects (92, 93) but is not a sufficient explanation in the absence of further kinetic details about particular reactions.…”
mentioning
confidence: 99%
“…Quinidine is not metabolized by CYP2D6 and has long been established as a potent competitive inhibitor of the enzyme (5)(6)(7)(8)(9). The fact that quinidine is an inhibitor rather than a substrate is intriguing because it produces a classical type I binding spectrum with CYP2D6 (10) that is usually associated with the binding of substrate molecules (11).…”
mentioning
confidence: 99%