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Vol. 27, Issue 9, 1024-1028, September 1999
) Bufuralol, the
Prototypic Substrate of CYP2D6
Central Research Division, Pfizer, Incorporated, Groton,
Connecticut
Upon characterization of baculovirus-expressed cytochrome P-450
(CYP) 2C19, it was observed that this enzyme metabolized (+/
) bufuralol to 1'hydroxybufuralol, a reaction previously understood to be
selectively catalyzed by CYP2D6. The apparent
Km for this reaction was 36 µM with
recombinant CYP2C19, approximately 7-fold higher than for recombinant
CYP2D6. The intrinsic clearance for this reaction was 37-fold higher
with CYP2D6 than for CYP2C19. The involvement of human CYP1A2 in
bufuralol 1'-hydroxylation was also confirmed using the recombinant
enzyme. Using S-mephenytoin as an inhibitor, the
Ki for inhibition of recombinant
CYP2C19-mediated bufuralol hydroxylation was 42 µM, which is the
approximate Km for recombinant
CYP2C19-mediated S-mephenytoin metabolism. The classic
CYP2D6 inhibitors quinidine and quinine showed no inhibition of
CYP2C19-catalyzed bufuralol metabolism at concentrations that abolished
CYP2D6-mediated bufuralol metabolism. Ticlopidine, a potent inhibitor
of CYP2C19 and CYP2D6, inhibited bufuralol 1'-hydroxylation by each of
these enzymes equipotently. In human liver microsomes that are known to
be deficient in CYP2D6 activity, it was shown that in the presence of
quinidine, the Km shifted from 14 to 38 µM. This is consistent with the Km
determination for recombinant CYP2C19 of 36 µM. In human liver
microsomes that have high CYP2D6 and CYP2C19 activity, the
Km shifted to 145 µM in the presence of
S-mephenytoin and quinidine, consistent with the
Km determined for CYP1A2. This data suggests
that bufuralol, and possibly other CYP2D6 substrates, have the
potential to be metabolized by CYP2C19.
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