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Vol. 60, Issue 2, 382-387, August 2001
Department of Medicinal Chemistry, University of Washington,
Seattle, Washington (L.J.D., A.E.R., M.B.K.); and Division of Clinical
Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt
University School of Medicine, Nashville, Tennessee (R.B.K., A.J.J.W.,
C.M.S., G.R.W., U.I.S.)
CYP2C9 is a polymorphic gene for
which there are four known allelic variants; CYP2C9*1,
CYP2C9*2, CYP2C9*3, and
CYP2C9*4. In the present study, DNA from 140 European
Americans and 120 African Americans was examined by single-strand
conformational polymorphism and restriction fragment length
polymorphism analyses, resulting in the identification of a new CYP2C9
variant, CYP2C9*5. This variant is derived from a C1080G
transversion in exon 7 of CYP2C9 that leads to an
Asp360Glu substitution in the encoded protein. The
CYP2C9*5 variant was found to be expressed only in African Americans, such that approximately 3% of this population carries the CYP2C9*5 allele. The variant was expressed
in, and purified from, insect cells infected with a recombinant
baculovirus. Comparative kinetic studies using the purified wild-type
protein CYP2C9*1; the Ile359Leu variant, CYP2C9*3; and the Asp360Glu
variant, CYP2C9*5 were carried out using (S)-warfarin,
diclofenac, and lauric acid as substrates. The major effect of the
Asp360Glu mutation was to increase the Km
value relative to that of CYP2C9*1 for all three substrates: 12-fold
higher for (S)-warfarin 7-hydroxylation, 5-fold higher
for the 4'-hydroxylation of diclofenac, and 3-fold higher for the 
-1
hydroxylation of lauric acid. Vmax values
differed less than Km values between the
CYP2C9*1 and CYP2C9*5 proteins. In vitro intrinsic clearances for
CYP2C9*5, calculated as the ratio of
Vmax/Km, ranged
from 8 to 18% of CYP2C9*1 values. The corresponding ratio for CYP2C9*3
was 4 to 13%. Accordingly, the in vitro data suggest that carriers of
the CYP2C9*5 allele would eliminate CYP2C9 substrates at
slower rates relative to persons expressing the wild-type protein.
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