Journal of Clinical Pharmacy and Therapeutics (2007) 32, 313–319

PHARMACOGENETICS

Single step PCR for detection of allelic variation of MDR1

gene (P-glycoprotein) among three ethnic groups in
Malaysia
L. K. Teh* PhD , W. L. Lee* ,  BPharm , J. Amir PharmD , M. Z. Salleh§ PhD and
R. Ismail PharmD
*Faculty of Pharmacy, Universiti Teknologi MARA, 41050 Shah Alam, Malaysia, Pharmacogenetics
Research Group, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia,
16150 Kubang Kerian, Kelantan, Malaysia, Department of Pharmacy, Faculty of Medicine, University of
Malaya, 50603 Kuala Lumpur, Malaysia and §Malaysian Biodiagnostic Research S/B, UKM-MTDC Smart
Technology Centre, Kuala Lumpur, Malaysia

groups. In comparison to both the Caucasians and

SUMAMRY
Background: P-glycoprotein (PgP) is the most
extensively studied ATP-binding cassette (ABC)
coded by MDR1 gene. To date, 29 single nucleo-
tide polymorphisms (SNPs) have been identified;
but only SNP C3435T has been correlated with
intestinal PgP expression levels and shown to
influence the absorption of orally taken drugs
that are PgP substrates. Individuals homozygous
for the T allele have more than fourfold lower
PgP expression compared with C/C individuals.
We developed a one step primer based allele
specific PCR method to detect SNP at C3435T to
investigate the distribution of this genotype in
the local population.
Method: DNA was extracted from 5 mL of whole
blood using standard salting-out method. Primers
were designed specific to 3¢ end which amplify
the variants of C3435T. The method was validated
by direct DNA sequencing. Seven hundred and
sixty-three healthy blood donors comprising of
three major ethnic groups in Malaysia were
recruited and DNA subjected to genotyping of
C3435T using this method.
Result: The method was found to be robust and
reproducible in detecting SNP of C3435T. Inter-
ethnic variations in genotype and allele fre-
quency were observed in PgP among the ethnic
Received 14 September 2006, Accepted 14 March 2007
Correspondence: Teh Lay Kek, PhD, Pharmacogenetics Research
Group, Faculty of Pharmacy, Universiti Teknologi MARA, 41050
Shah Alam, Malaysia. Tel.: +603 5544 2875; fax: +603 5544 2725;
e-mail: tehlaykek@salam.uitm.edu.my
the other Asian countries, the Malay and Chinese
showed a higher frequency of allele C (50–60%);
while the Indian exhibits a lower frequency
(40%), similar to other Indian populations.
Discussion and conclusion: Using a new simple
method to investigate the distribution of C3435T,
we found that the allele frequency of MDR1
showed variablity between the different ethnic
groups within the Malaysian population.
Keywords: C3435T polymorphism, Chinese,
Indians, Malays, MDR1, P-glycoprotein
INTRODUCTION
P-glycoprotein (PgP), the product of the multidrug
resistance gene (MDR1), is the most extensively
studied ATP-binding cassette (ABC). It acts as an
energy-dependent efflux pump that exports its
substrates out of the cell. The differential expres-
sion of the PgP suggests that the efflux transporter
can functionally protect the body against toxic
xenobiotics by excreting these compounds into bile,
urine and the intestinal lumen, and by preventing
their accumulation in the brain. PgP may play a
significant role in absorption, distribution, meta-
bolism and excretion of drugs including many
chemotherapeutic agents (1), cardiac glycosides (2),
HIV-1 protease inhibitors (3), and cyclosporine (4).
To date, 29 single nucleotide polymorphisms
(SNPs) have been identified in the entire human
MDR1 gene (5). The genetic variant C3435T in exon

 2007 The Authors. Journal compilation  2007 Blackwell Publishing Ltd 313
314 L. K. Teh et al.
26 is a synonymous polymorphism and has been
associated with intestinal PgP expression levels
and shown to influence the absorption of orally
taken drugs that are PgP substrates (6, 7). How-
ever, there have been conflicting reports indicating
that functional effects of the C3435T SNP may not
be genotype- but haplotype-dependent with the
polymorphism G2677T in exon 21 and C1236T (8).
It is unclear how C3435T variant, a synonymous
SNP caused altered PgP expression until Wang
et al. (9) confirmed in their cell transfection
experiment that only C3435T was the functional
SNP causing allelic differences in the expression of
MDR1 by changing the mRNA stability (9).
As over-expression of PgP has been associated
with altered drug absorption, therapy-resistant
malignancies, and lower concentrations of HIV-1
protease inhibitors (3), genotyping for poly-
morphism of C3435T may provide a useful
approach to individualize therapy. Information
gathered on the distribution of this C3435T poly-
morphism in populations of different ethnic origin
may contribute to explaining interindividual and
interethnic differences in drug response and/or
side-effects. We thus studied the distribution of this
genotype in the multi-ethnic Malaysian population.
MATERIALS AND METHODS
Subjects
The protocols for this study, approved by the
Ethical Committee of Universiti Sains Malaysia,
complied with the declaration of Helsinki. The
study was part of a larger study aimed at compi-
ling local data banks on the genetic polymorphism
of drug metabolizing enzymes and receptors. In
this study, 763 healthy blood donors were recruited
Table 1. Primers sequences, respective location and concentration of first and second PCR for detection of MDR1
C3435T polymorphism
Accession
Primer Sequence no.
Ex26Fw 5¢-tgt ttt cag ctg ctt gat gg-3¢ M29445
Ex26Rv 5¢-aag gca tgt atg ttg gcc tc-3¢ M29445
3435CRv 5¢-ctt tgc tgc cct cac g-3¢ M29445
3435TRv 5¢-ctt tgc tgc cct cac a-3¢ M29445
 2007 The Authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 313–319
during blood donation campaigns in Kuala Lum-
pur, walk-in blood donors at the Universiti Malaya
Medical Centre (UMMC) in Kuala Lumpur, Uni-
versiti Malaya and Universiti Sains Malaysia
undergraduate students and residents of a Malay-
sian Indian community in Kelantan. Subjects were
enquired about their medical history and origin up
to three generations. Five millilitres of blood was
taken from each subject after written-informed
consent was obtained. Leucocytes DNA
was extracted according to method described
earlier (10).
One step PCR genotyping of C3435T
A simple PCR method was developed to detect the
presence of the variant of C3435T. Two pairs of
PCR primers were used in the parallel reaction to
identify the single nucleotide difference at 3435 of
MDR1 (Accession number: M29445). The first pair
was adapted from Cascorbi et al. (11) to amplify
exon 26 specifically. The second pair was a com-
mon primer (Ex26Fw) and an allele specific primer
at the 3¢ end, manipulated to differentiate single
nucleotide changes at the specific locus during PCR
amplification. In order to avoid incompatibility of
the primers sets, they were designed to have sim-
ilar annealing temperatures with appropriate
lengths and GC contents. The primers were
designed manually and the initial annealing
temperature was determined using the formula
‘Tm = [2(A + T) + 4(C + G)]’. Table 1 shows the
primers used for the nested PCR.
We varied the concentrations of Taq polymerase
and MgCl2 to obtain specific PCR products. The
other important parameter that was tested was
annealing temperature and primer concentration.
The concentrations of each set of primers were
Primer
Amplicon Calculated concentration
Location Size (bp) Tm (C) (lM) References
15–34 196 58 0Æ3 11
192–211 60 0Æ06 11
176–192 177 52 0Æ25 Current
176–192 50 0Æ25 Current
 Allelic Variation of MDR1 Gene among Malaysians 315

varied in steps until maximum sensitivity and
specificity were obtained (Table 1).
The final PCR protocol comprised of 25 lL
reaction mixture of 1 · PCR buffer (Biotools, B & M
Labs, S.A., Madrid, Spain), 2Æ0 mmol/L MgCl2,
0Æ2 mmol/L dNTP (Promega Corporation,
Madison, WI, USA), primer concentrations as
shown in Table 1, 200 ng (2 lL) genomic DNA as
template and 1Æ0 U DNA Taq polymerase (Biotool).
The PCR were performed with an initial hot start
at 94 C for 5 min, followed by ten cycles of
denaturation at 94 C for 30 s, annealing at 61 C for
30 s and extension at 72 C for 20 s. The PCR was
continued with another 25 cycles of denaturation at
94 C for 30 s, annealing at 55 C for 30 s and
extension at 72 C for 20 s using GeneAmp PCR
system 2700 Perkin Elmer (Applied Biosystems,
Roche Molecular Systems Inc., Branchburg, NJ,
USA).
The PCR products were electrophoresed on an
ethidium bromide stained, 3% agarose gel (LE,
analytical grade; Promega Corporation, Madison,
WI, USA) in 1X TBE (Tris, Borate, EDTA) buffer at
100 Volt for 45 min.

PSY010 PSY012 PSY015 PSY016 PSY017

WT Vr WT Vr WT Vr WT Vr WT Vr

Nucleotide confirmed as T at 3425

Nucleotide confirmed as C and T at 3435

Fig. 1. Sequencing result for two

samples. PSY015 was genotyped as
homozygous T3435T while PSY016
as heterozygous C3435T. Both
samples were sequenced to confirm
the genotyping result.

 2007 The Authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 313–319
316 L. K. Teh et al.

genotyped all the samples. The method was

Direct PCR sequencing
The optimized nested PCR method was tested ini-
tially with 50 unknown DNA samples. A total of
nine samples (three of each genotype) were selec-
ted randomly and reconfirmed by direct sequen-
cing before the method was used to screen the
remaining samples. They were subsequently used
as positive controls in large DNA samples screen-
ing. The DNA samples were purified using QIA-
quickR PCR Purification Kit (Qiagen, Hilden,
Germany) and sequenced on ABI 3700 using Big
Dye Terminator Cycle Sequencing Ready Reaction
Kit (Applied Biosystems).
Two independent gel reviewers were employed
to analyse the gel-documented result to ensure
unequivocal result. Repeats were done for samples
that did not have clear bands or have equivocal
results. An analysis was scored as unsuccessful
amplification if the repeat failed.
Statistical analysis
Data were compiled according to the genotype
and allele frequencies with the 95% confidence
intervals (p ± 1Æ96p(1-p)/n). Expected geno-
type frequencies were calculated using the Hardy–
Weinberg equation (p2 + 2pq + q2 = 1); where p is
the frequency of C and q for T at 3435 nucleotide of
MDR1. The chi-squared test was used to compare
the genotype frequencies in the three populations.
A P-value of 0Æ05 or less was regarded as significant.
sensitive and specific in discriminating variants
C from T and the result was confirmed by sequen-
cing (Fig. 1).
The 763 healthy volunteers recruited comprised
66% males (Table 2). DNA was successfully
extracted from all the samples and subjected to
genotyping of C3435T. Using this method, MDR1
C3435T variants were detected in all three Malay-
sian races. About half of the Malaysian Malays and
Chinese were heterozygous carriers of the C/T
variant; while 44% of the Indians had the same
genotype. The Indian have more than twofold
higher frequency of homozygous TT variant (40%)
compared to the Malays and Chinese (15% and
14% respectively).
The predicted frequencies of MDR1 C3534T
genotypes among three Malaysian races were cal-
culated according to the Hardy–Weinberg equation
together with its 95% confidence intervals (CI) as
shown in Table 3. The genotypes were found to be
in equilibrium. In comparison to frequencies
reported for Caucasians and some other Asian
countries, the Malay and Chinese showed a higher
frequency of allele C (50–60%); while the Indian
exhibited a lower frequency (40%). The frequency
distributions of the genotype were similar among
the Malays and Chinese (Pearson chi-square,
P = 0Æ906) but different from the Indians (Pearson
chi-square, P = 0Æ000) within the same community.
DISCUSSION

The on- step-primer-based allele specific PCR

RESULTS
method developed was found to be simple and
The simple one-step PCR method for the determin- allowed detection of the SNP at C3435T. It is more
ation of SNP, MDR1 C3435T variants successfully economical and suitable for use in large studies

Table 2. Demographic data and genotype frequency of the studied group

3435 C/T of MDR1

Ethnic Sex n Age (years ± SD) C/C C/T T/T Pearson chi-square; P

Malay $ 177 29Æ2 ± 7Æ8 66 78 33 0Æ065

# 127 25Æ9 ± 6Æ8 44 70 13
Chinese $ 197 29Æ9 ± 9Æ0 77 98 22 0Æ133
# 91 27 ± 8 30 43 18
Indian $ 126 27Æ2 ± 9Æ7 21 55 50 0Æ971
# 45 23Æ5 ± 5Æ8 8 20 17

 2007 The Authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 313–319
 Allelic Variation of MDR1 Gene among Malaysians 317

Table 3. Allele frequency together with the observed and predicted genotype frequencies* of MDR1 C3435T variants in
three major races in Malaysia

Frequency (%) ± 95% CI

Ethnic groups Frequency
(Sample size) Allele (%) ± 95% CI Genotype Observed Predicted References

Malay (n = 304) C 60Æ53 ± 3Æ89 C/C 36Æ18 ± 5Æ4 36Æ63 ± 5Æ42 Current
T 39Æ47 ± 3Æ89 C/T 48Æ68 ± 5Æ62 47Æ78 ± 5Æ62
T/T 15Æ13 ± 4Æ03 15Æ58 ± 4Æ08
Malay (n = 99) C 47Æ98 ± 6Æ96 C/C 25Æ25 ± 8Æ56 23Æ02 ± 8Æ29 16
T 52Æ02 ± 6Æ96 C/T 46Æ46 ± 9Æ82 49Æ92 ± 9Æ85
T/T 28Æ28 ± 8Æ87 27Æ09 ± 8Æ75
Chinese (n = 288) C 61Æ63 ± 3Æ97 C/C 37Æ15 ± 5Æ58 37Æ98 ± 5Æ61 Current
T 38Æ37 ± 3Æ97 C/T 48Æ96 ± 5Æ77 47Æ27 ± 5Æ77
T/T 13Æ89 ± 3Æ99 14Æ72 ± 4Æ09
Chinese (n = 98) C 45Æ92 ± 6Æ98 C/C 24Æ49 ± 8Æ51 21Æ09 ± 8Æ08 16
T 54Æ08 ± 6Æ98 C/T 43Æ88 ± 9Æ82 49Æ67 ± 9Æ90
T/T 31Æ63 ± 9Æ21 29Æ25 ± 9Æ01
Chinese (n = 132) C 53Æ03 ± 6Æ02 C/C 31Æ82 ± 7Æ95 28Æ12 ± 7Æ67 17
T 46Æ97 ± 6Æ02 C/T 42Æ42 ± 8Æ43 49Æ82 ± 8Æ53
T/T 25Æ76 ± 7Æ46 21Æ64 ± 7Æ02
Indian (n = 171) C 38Æ89 ± 5Æ17 C/C 16Æ96 ± 5Æ62 15Æ12 ± 5Æ37 Current
T 61Æ11 ± 5Æ17 C/T 43Æ86 ± 7Æ44 47Æ53 ± 7Æ49
T/T 39Æ18 ± 7Æ32 37Æ35 ± 7Æ25
Indian (n=87) C 38Æ17 ± 6Æ98 C/C 18Æ28 ± 7Æ86 14Æ57 ± 7Æ41 16
T 61Æ83 ± 6Æ98 C/T 38Æ71 ± 9Æ90 47Æ20 ± 10Æ49
T/T 43Æ01 ± 10Æ06 38Æ23 ± 10Æ21
Caucasian, UK (n = 190) C 47Æ89 ± 5Æ03 C/C 27Æ89 ± 6Æ38 22Æ93 ± 5Æ98 17
T 52Æ11 ± 5Æ02 C/T 47Æ89 ± 7Æ10 49Æ91 ± 7Æ11
T/T 24Æ21 ± 6Æ09 27Æ15 ± 6Æ32
African American (n = 88) C 84Æ09 ± 5Æ41 C/C 68Æ18 ± 9Æ73 70Æ71 ± 9Æ51 17
T 15Æ91 ± 5Æ40 C/T 30Æ68 ± 9Æ64 26Æ76 ± 9Æ25
T/T 1Æ14 ± 1Æ13 2Æ53 ± 3Æ28
Ghanaian (n = 206) C 83Æ01 ± 3Æ63 C/C 66Æ99 ± 6Æ42 68Æ91 ± 6Æ32 17
T 16Æ99 ± 3Æ63 C/T 33Æ01 ± 6Æ42 28Æ21 ± 6Æ15
T/T 0 2Æ89 ± 2Æ29
Saudi n = 96) C 55Æ21 ± 7Æ03 C/C 36Æ46 ± 9Æ63 30Æ48 ± 9Æ21 17
T 44Æ79 ± 7Æ04 C/T 37Æ50 ± 9Æ68 49Æ45 ± 10Æ0
T/T 26Æ04 ± 8Æ78 20Æ06 ± 8Æ01

*Predicted genotype frequencies are calculated from the allelic frequency according to Hardy–Weinberg equation.

compared with genotyping using restriction
enzymes. The primers were designed with due
consideration to the homology of the primers with
regard to their target sequences, the lengths of the
primers and their GC contents, factors important to
obtain a specific method.
We optimized parameters including the con-
centrations of magnesium and Taq, as well as
annealing temperature to increase specificity of the
method. Besides the PCR cycling conditions and
PCR mix, the concentration of primers was found
to be a particularly sensitive parameter affecting
specificity. The optimized method was found to be
reproducible and specific when tested against 50
DNA samples. A total of nine samples (three
of each genotype) were selected randomly and
reconfirmed by direct sequencing before the
method was used to screen the remaining samples.
We employed the random use of two independent
blinded gel reviewers for quality assurance. Similar

 2007 The Authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 313–319
318 L. K. Teh et al.
to the reported ethnic variation in the polymorph-
ism of CYP (10, 12– 15), interethnic differences in
MDR1 polymorphisms were observed among the
three Malaysia ethnic groups. Our study showed
C/C (wild type) allele frequencies of 60–62% in the
Malays and Chinese, and 40% in the Indians. The
genotype frequencies of C3435T were significantly
different between the Malays and Indians and
between Chinese and Indians but no significant
differences were seen between the Malays and the
Chinese (Pearson chi-square, P = 0Æ906). The fre-
quency of C3435C among the Malays and Chinese
in our community although higher than those
reported by Balram et al. (16), was not significantly
so.
Marked differences in genotype and allele
frequency have been reported for the C3435T
polymorphism in exon 26 between African and the
Caucasian/Asian populations (16, 17). The Gha-
naian, Kenyan, African–American and Sudanese
populations have the highest frequencies (70–80%),
thus far reported for the C/C (wild type) allele (17).
In contrast, British Caucasian, Portuguese, South-
west Asian, Chinese, Filipino and Saudi popula-
tions have lower frequencies of the C/C allele,
ranging from 34–55% (17).
Although the available clinical data are still
limited, Hoffmeyer et al. (18) showed that subjects
carrying the C/C genotype had lower steady-state
maximum plasma concentrations of digoxin com-
pared with T/T subjects and this was due to higher
duodenal expression of PgP in C/C subjects. The
higher PgP expression in African populations was
thought to contribute to variability in clinical
response to cyclosporine and HIV protease inhibi-
tors as well as resitance against viral infections,
especially in the cellular uptake of virus particles
and virus production (19). This is because over
expression of PgP could result in reduction of
susceptibility of human CD4+ cells to infection with
HIV-1. On the other hand it may result in restricted
access of HIV-1 protease inhibitors to CD4+ cells
and lower bioavailability of cyclosprin A among
Africans (20). However, further studies are needed
to clarify the mechanism by which decreased PgP
expression might affect susceptibility to infectious
diseases and response to drug treatment with its
substrates.
In summary, as C3435T SNP appears to be a
main factor in allelic variation of MDR1 mRNA
 2007 The Authors. Journal compilation  2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 313–319
expression in the liver (9), this single step PCR
method would be useful for population or
clinical studies. Identification of different MDR1
alleles in patients may provide a useful tool for
optimizing therapy with PgP substrates, inclu-
ding digoxin, many antiviral compounds and
cyclosporine.
ACKNOWLEDGEMENT
This study was supported by grant from the
‘Intensified Research Priority Areas’ from the
Ministry of Science, Technology and Innovation of
Malaysia.
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