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Technical Briefs |
1
Psychiatry and
2
Biochemistry, The Chinese University of Hong Kong, Hong Kong;
a author for correspondence: fax 852-2646-2284, e-mail b025744{at}mailserv.cuhk.edu.hk
A genetic polymorphism in the metabolism of the anticonvulsant
drug mephenytoin in humans is a prime example of interracial and
individual variability in drug metabolism. This polymorphism affects
the metabolism of several other clinically used drugs, some of which
are of interest in psychopharmacotherapy (1). The
polymorphic enzyme that 4'-hydroxylates S-mephenytoin is
known as CYP2C19 (2). In subjects deficient for CYP2C19,
drugs metabolized by this enzyme may be associated with toxic
concentrations or therapeutic failure when administered in dosages
within the normal dosage range. Depending on the activity of
CYP2C19, individuals can be characterized phenotypically as extensive
metabolizers or poor metabolizers (PMs) of
S-mephenytoin. CYP2C19 is encoded by the CYP2C19
gene, and its defective alleles account for the PM phenotype, which is
inherited as an autosomal recessive trait (3). There is a
marked interethnic difference in the distribution of this polymorphism,
with the PM phenotype found in 2–5% of Caucasians but in 13–23% of
Orientals (4)(5). The main defective allele,
CYP2C192, accounts for ~75–85% of alleles responsible
for the PM phenotype in both Orientals and Caucasians (4).
CYP2C193 is extremely rare in the Caucasian population but
accounts for almost all of the remaining defec- tive alleles in
Orientals (3)(4)(5)(6)(7)(8)(9). Subsequent studies have revealed
additional defective CYP2C19 alleles in Caucasian PMs,
identifying 
93% of the defective alleles: CYP2C192B
(10), CYP2C194 (9),
CYP2C195B (11), and CYP2C196
(10). Only one new allele, CYP2C195A
(7), has been found in the Chinese Bai population at a very
low frequency (0.0025). In addition to the interracial differences in
the genetic polymorphism of the CYP2C19 enzyme, Xiao et al.
(7) showed a different incidence of the CYP2C192
and CYP2C191 alleles in two Chinese ethnic groups. These
differences in allele frequencies were consistent with phenotypic data
suggesting that different Chinese ethnic groups may exhibit somewhat
different sensitivities to drugs metabolized by CYP2C19. Therefore, it
was of interest to us to investigate the CYP2C19 genotype in
a Hong Kong Chinese population.
One hundred nineteen unrelated Hong Kong Chinese individuals participated in the genotyping tests. Forty-five patients diagnosed with depressive disorders according to Diagnostic and Statistical Manual IV but without impairment in liver or kidney function, and 74 healthy subjects were included in this study after giving their informed consent. This research project has been approved by the ethics committee of the Chinese University of Hong Kong.
Blood samples (12 mL) were collected in Vacutte® (Greiner) tubes containing EDTA as anticoagulant. DNA was extracted using the Qiamp Blood kit (Qiagen). PCR followed by restriction enzyme analysis of the amplified products was used to identify CYP2C19 alleles as described previously (7)(8)(9)(11).
Binomial probabilities were used to compute the exact confidence
intervals for the frequencies. Allele frequencies in different
populations were compared with the 
2 test.
The allele frequencies are listed in Table 1
. In general, our data were in
agreement with the incidence of CYP2C19 alleles reported
previously for other Chinese Han populations (Table 1
). The frequency
of the wild-type allele (CYP2C191) appears marginally
higher than that found by Xiao et al. (7) for the Chinese
Han population studied (2 = 3.872;
P = 0.051).
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CYP2C192, CYP2C193, and CYP2C195
have been shown to account for >99% of the defective
CYP2C19 alleles in the three main Oriental races, indicating
a complete concordance between phenotype and genotype
(5)(8). This suggests that other defective
alleles are unlikely to contribute to the PM phenotype in these
populations. Surprisingly however, one subject (C33) harbored a
CYP2C194 allele (Fig. 1
). To our knowledge, this is the first CYP2C194
allele found in a Chinese individual. CYP2C194 accounted
for the predicted phenotype of one PM individual, with a
CYP2C192/CYP2C194 genotype, and represented 2.38% of the
defective alleles in the PMs.
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Twenty-one subjects (17.65%) were genotypically identified as PMs. The
incidence of PM genotypes is comparable to the incidences reported for
other Chinese groups (Table 1
)
(5)(7)(12)(13).
CYP2C192 and CYP2C193 accounted for 80.95% and
16.66%, respectively, of the defective alleles in the 21 PMs. We did
not detect any occurrence of the alleles CYP2C195
(5A, 5B) (7)(11).
The incidence of PMs found in this study differs only from that found
in Chinese Dong subjects, which was estimated as 11.1% (17.65%;
2 = 3.02; P = 0.01). The different
incidences of PM for different Chinese ethnic groups may reflect
differences in sample size and/or in methods. However, further studies
on larger samples should be carried out.
In summary, our data were generally in agreement with the prevalence of PMs in the Chinese populations previously genotyped and phenotyped except for the detection of the CYP2C194 allele.
Acknowledgments
We thank R. J. Morgan for reading this article and for helpful comments and criticisms.
References
The following articles in journals at HighWire Press have cited this article:
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  O. Q. P. Yin, B. Tomlinson, A. H. L. Chow, M. M. Y. Waye, and M. S. S. Chow Omeprazole as a CYP2C19 Marker in Chinese Subjects: Assessment of Its Gene-Dose Effect and Intrasubject Variability J. Clin. Pharmacol., June 1, 2004; 44(6): 582 - 589. [Abstract] [Full Text] [PDF]
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 J. Borlak and T. Thum Identification of Major CYP2C9 and CYP2C19 Polymorphisms by Fluorescence Resonance Energy Transfer Analysis Clin. Chem., September 1, 2002; 48(9): 1592 - 1594. [Full Text] [PDF]
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