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Vol. 52, Issue 6, 1034-1040, 1997
Department of Medical Biochemistry and Biophysics and Division of
Molecular Toxicology, Institute of Environmental Medicine, Karolinska
Institutet, 171 77 Stockholm, Sweden
In many black African populations, the capacity for CYP2D6-dependent
drug metabolism is generally reduced. A specific variant of the
CYP2D6 gene (CYP2D6*17) that carries
three functional mutations (T107I, R296C, and S486T) has been found to
be present in Zimbabwean subjects with impaired CYP2D6-dependent
hydroxylase activity. To evaluate whether the CYP2D6*17
allele was the major cause behind the decreased rate of drug metabolism
and to examine the role of the different mutations, CYP2D6 cDNAs
containing all eight combinations of the mutations were created.
Expression of the cDNAs in COS-1 cells revealed that the CYP2D6 17 enzyme displayed only 20% of the wild-type (CYP2D6 1) activity,
whereas the T107I substitution on its own had no significant effect on
enzyme function. Expression in yeast showed that the three possible
single amino-acid mutant CYP2D6 variants all had properties similar to
CYP2D6 1 when the kinetics of bufuralol hydroxylation was examined.
However, enzymes containing both the T107I and R296C mutations
exhibited a more than 5-fold higher
Km for bufuralol than the
wild-type enzyme, whereas the S486T mutation was of little importance.
In contrast, when codeine was used as a substrate, the T107I
substitution alone was sufficient to cause a significant increase in
the apparent Km, indicating a
differential effect for this substitution depending on the CYP2D6
substrate. In conclusion, the CYP2D6*17 allele
represents the first human cytochrome P450 polymorphic variant in which
a combination of substitutions is required to alter the enzyme's
catalytic properties and is the first case in which a decreased CYP2D6
activity, as monitored in vivo, has been documented to
be caused by an enzyme with altered affinity for CYP2D6 substrates.
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