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Rat CYP2D2, not 2D1, is functionally conserved with human CYP2D6 in endogenous morphine formation
Author(s) -
Grobe Nadja,
Kutchan Toni M.,
Zenk Meinhart H.
Publication year - 2012
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2012.05.021
Subject(s) - thebaine , chemistry , recombinant dna , cyp2d6 , codeine , stereochemistry , demethylation , phenethylamine , enzyme , microbiology and biotechnology , morphine , biochemistry , cytochrome p450 , biology , pharmacology , gene expression , dna methylation , gene
The assumption that CYP2D1 is the corresponding rat cytochrome to human CYP2D6 has been revisited using recombinant proteins in direct enzyme assays. CYP2D1 and 2D2 were incubated with known CYP2D6 substrates, the three morphine precursors thebaine, codeine and ( R )‐reticuline. Mass spectrometric analysis showed that rat CYP2D2, not 2D1, catalyzed the 3‐ O ‐demethylation reaction of thebaine and codeine. In addition, CYP2D2 incubated with ( R )‐reticuline generated four products corytuberine, pallidine, salutaridine and isoboldine while rat CYP2D1 was completely inactive. This intramolecular phenol‐coupling reaction follows the same mechanism as observed for CYP2D6. Michaelis–Menten kinetic parameters revealed high catalytic efficiencies for rat CYP2D2. These findings suggest a critical evaluation of other commonly accepted, however untested, CYP2D1 substrates.