DEXTROMETHORPHAN METABOLISM IN MEXICAN AMERICANS

10.1177/0091270005280755
PHARMACOGENOMICS
CASNER

The Effect of CYP2D6

Polymorphisms on Dextromethorphan
Metabolism in Mexican Americans
Paul R. Casner, MD, PhD

CYP2D6 is one of the most polymorphic of the cytochrome

P450 enzymes. Genetic differences in this enzyme have been
reported in whites, blacks, and Asians. However, there is very
little information about polymorphisms of this enzyme in
Mexican Americans. The objectives of the present study were
to assess the metabolic activity of CYP2D6 in a Mexican
American population using dextromethorphan and to correlate this metabolic activity with a genotypic analysis. The
sample consisted of 50 Mexican American subjects and 25
nonMexican American controls. Overnight urine samples
were collected and analyzed by high-performance liquid
chromatography to calculate the metabolic ratio of
dextromethorphan to dextrorphan. Blood samples were col-

lected for genotypic analysis of CYP2D6 alleles. The frequency of the poor metabolizer phenotype was the same in
the Mexican American group and the nonMexican American group (6% vs 5.5%). The frequency of alleles in the Mexican American group was similar to frequencies published in
other reports for non-Hispanic whites: *4 = 0.17, *5 = 0.02,
*10 = 0.01, *17 = 0.02, *xN = 0.03. These results indicate that
compared with non-Hispanic whites, Mexican Americans
have a similar proportion of poor metabolizer phenotype and
similar genetic polymorphisms of CYP2D6.

cause of specific mutations in the enzyme.5 Asians, on

the other hand, have very low rates of poor metabolizers
(less than 1%).5 Some studies in blacks have shown
that up to 29% of studied populations are ultrarapid
metabolizers.6,7 Thus, it is apparent that there can be a
significant degree of genetic variation in the activity of
the CYP2D6 enzyme, depending on the racial or ethnic
makeup of the population.1
There have been very few studies looking at the activity of CYP2D6 in Hispanics. Some of these studies
were performed in Hispanics of European origin, that
is, in Spaniards,8,9 and 1 study was performed in Nicaraguans.10 There is only 1 study describing CYP2D6 genotype and phenotype activity in Mexican Americans.11 The rapid growth of the Mexican American
population in the United States underscores the need
for continued studies that analyze drug-metabolizing
characteristics of this minority population, which is
currently the largest in the United States.12 The present
study examined the phenotypic and genotypic characteristics of CYP2D6 in Mexican Americans living in the
border region of El Paso, Texas.

characteristic feature of drug action in individual

patients is the variability of drug metabolism from
one patient to another. This variability is related to
well-known factors such as age, gender, environment,
and genetics.1 Individual patients can be categorized
according to the rate of drug metabolism as either poor
metabolizers, extensive metabolizers, and in some situations, ultrarapid metabolizers.2 Minor alterations in
the amino acid makeup of a cytochrome P450 enzyme
may result in altered metabolic activity. Several
cytochrome P450 enzymes exhibit a great deal of genetic polymorphisms. The CYP2D6 enzyme has more
than 80 alleles3 and is involved in the metabolism of
more than 50 medications.4
About 5% to 10% of whites are poor metabolizers of
the drugs that the CYP2D6 enzyme metabolizes beFrom the Department of Internal Medicine, Texas Tech University Health
Sciences Center, El Paso, Texas. Submitted for publication April 12, 2005;
revised version accepted July 23, 2005. Address for reprints: Paul R.
Casner, MD, PhD, Department of Internal Medicine, Texas Tech University
Health Sciences Center, El Paso, TX 79905.
DOI: 10.1177/0091270005280755

1230 J Clin Pharmacol 2005;45:1230-1235

Keywords: CYP2D6; pharmacogenetics; Mexican American

Journal of Clinical Pharmacology, 2005:45:1230-1235
2005 the American College of Clinical Pharmacology

DEXTROMETHORPHAN METABOLISM IN MEXICAN AMERICANS

METHODS

Table I Demographic Dataa

Subjects
A total of 75 subjects participated in this study. The
study group consisted of 50 Mexican American participants and 25 nonMexican American participants who
served as controls. To qualify for the study, participants
had to be healthy, without any significant medical
problems, nonsmokers, and without a history of alcohol or drug use. A questionnaire was used to evaluate
health status, medication use, and ethnic background.
Patients were asked whether they considered themselves to be Hispanic. Participants were also asked
about their country of birth, their race, and whether
their parents and grandparents were born in Mexico.
For the purposes of this study, participants were considered to be Mexican American if they self-rated
themselves as such. The demographic characteristics
of the patient sample are indicated in Table I. This
study was approved by the Institutional Review Board
at the Texas Tech University Health Sciences Center, El
Paso campus.
Phenotyping
The dextromethorphan metabolic ratio (MR) was calculated as the ratio of the molar amount of the dextromethorphan to that of dextrorphan in the urine after an
overnight 8-hour collection. The dextromethorphan
MR is reported as log10. Subjects were instructed to
empty their bladder and then ingest 30 mg dextromethorphan (Whitehall-Robbins, Madison, NJ). Patients were instructed to transport the collected urine
sample to the study center in a precooled cooler. Urine
volume was measured and aliquots of urine samples
were stored at 70C until assayed. Dextromethorphan and dextrorphan levels were assayed by highperformance liquid chromatography analysis by a commercial laboratory (PPD Development, Middleton, Wis)
according to the methodology of Bartoletti et al.13
Interassay coefficients of variation were 1.63% to
2.29% for dextrorphan and 1.17% to 2.70% for dextromethorphan. Intraassay coefficients of variation were
1.1% to 8.4% for dextrorphan and were 2.84% to
10.3% for dextromethorphan. The lower limit of detection for dextrorphan was 0.1 g/mL and 0.01 g/mL
for dextromethorphan. The upper limit of detection
for dextrorphan was 2.0 g/mL and 2 g/mL for
dextromethorphan.

PHARMACOGENOMICS

Age
Gender
Male
Female
Birthplace
Mexico
United States
Other
Race
White
Asian
Black
Otherc
No. of relatives
born in Mexicod
6
5
4
3
2
1
0

Mexican
American

Control
(NonMexican American)

36.5 10.1b

42.9 8.6

11 (22)
39 (78)

12 (48)
13 (52)

16 (32)
34 (68)
0

0
16 (64)
9 (36)

40 (80)
0
0
10 (20)

18 (72)
6 (24)
1 (4)
0

23 (46)
4 (8)
5 (10)
3 (6)
6 (12)
7 (14)
2 (4)

a. Age data are presented as mean SD; all other data are presented as n (%).
b. Significantly different from control, P < .05.
c. Native American, 1; no answer, 4; Mestizo, 5 (the term Mestizo refers to a
person of mixed Spanish and Native American ancestry.
d. Parents and grandparents (maternal and paternal).

Genotyping
Ten milliliters of venous blood was collected from each
study participant. Blood was collected in tubes containing ethylenediamine tetraacetic acid, frozen and
stored at 70C until DNA extraction. A commercial
laboratory (PPGx Inc, Morrisville, NC) performed the
genotyping. The following alleles were assayed by
polymerase chain reaction (PCR) analysis: *3, *4, *5,
*6, *7, *8, *10, *17, *xN.
Samples were processed for CYP2D6 *3, *4, *6, *7,
and *8 alleles by multiplex PCR using previously described assay techniques.14 The *5 allele was analyzed
by a long-range PCR method.15,16 The *xN allele was assayed by a long-range PCR method to amplify a 3.2
kilobase product specific for the duplicated locus.17
The *10 and *17 alleles were identified by allelespecific assays according to Wang et al 18 and
Masimirembwa et al.19

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CASNER

Statistical Analysis
Statistical comparisons were made using the Students
t test and the Mann-Whitney U test. Allele frequencies
were compared using the Fishers exact test. To determine contributing factors to the MR, a multiple regression model was constructed using the MR as the dependent variable. Sample differences were considered
to be statistically significant for P < .05. Statistical analysis was performed using a statistical software package
(NCSS Statistical System for Windows, Kaysville,
Utah).

Table II CYP2D6 Allele Frequencies

Allele

Mexican
American
n = 50

*4
*5
*10
*17
*xN

17 (0.17)
2 (0.02)
1 (0.01)a
2 (0.02)
3 (0.03)

CI

Control
(NonMexican
American)
n = 25

CI

0.10-0.26
0.00-0.070
0.00-0.050
0.00-0.070
0.01-0.09

9 (0.18)
1 (0.02)
4 (0.08)
1 (0.02)
1 (0.02)

0.09-0.31
0.00-0.11
0.02-0.19
0.00-0.11
0.00-0.11

Data are presented as number (frequency); CI = 95% confidence interval.

a. Significantly different from control, P < .05.

RESULTS
Demographic data for the experimental and control
groups are shown in Table I. The Mexican American
study participants were younger than the non
Mexican American control group (P < .05). The Mexican American group had a higher percentage of females
(78% vs 52%). The majority of Mexican Americans
were born in the United States (68%) as opposed to
Mexico (32%). Eighty percent considered themselves
white. Approximately 65% of the Mexican American
group had at least 4 relatives (ie, parents or grandparents) born in Mexico; 46% had both parents and both
sets of grandparents born in Mexico.
The allele frequencies for the Mexican American
group were similar to the white nonMexican American group and similar to established allele frequencies
for whites (Table II). The *10 allele frequency in the
control group was significantly higher than in the Mexican American group. This finding is because 24% of
the control group subjects identified themselves as
Asian (Table I). There were 3 poor metabolizers in the
Mexican American group (two *4/*4, one *4/*5) and 1
poor metabolizer in the nonMexican American group
(*4/*4). The *4 allele was the most common allele,
with a frequency of 0.17. None of the Mexican American subjects had *3, *6, *7, or *8. Genotype frequencies
are shown in Table III, with the most common variant
genotype being *4/wt.
The MR for dextromethorphan-dextrorphan was
able to separate the poor metabolizer by using the established antimode of the dextromethorphandextrorphan MR for whites (0.3, log10 = 0.53) (Figure
1). The poor metabolizer frequency in the Mexican
American group was 6% versus 5.5% in the non
Mexican American group. The mean MR of the Mexican American group as a whole was 2.34 (95% confidence interval [CI] = 2.06 to 2.62), whereas the MR of
the extensive metabolizers was 2.54 (95% CI = 2.35
to 2.72). These values were not significantly different
1232 J Clin Pharmacol 2005;45:1230-1235

Table III CYP2D6 Genotype Frequencies

Genotype

Mexican
American
n = 50

*4/wt
*4/*4
*4/*5
*4/*10
*5/wt
*10/wt
*10/*10
*17/wt
*xN
*xN/*4
*xN/*17

10 (0.20)
2 (0.04)
1 (0.02)

1 (0.02)
1 (0.02)

2 (0.04)
1 (0.02)
2 (0.04)

CI

0.10-0.34
0.01-0.14
0.00-0.11
0.00-0.11
0.00-0.11
0.01-0.14
0.00-0.11
0.01-0.14

Control
(NonMexican
American)
n = 25

6 (0.24)
1 (0.04)

1 (0.04)
1 (0.04)
1 (0.04)
1 (0.04)

1 (0.04)

CI

0.09-0.45
0.00-0.20
0.00-0.20
0.00-0.20
0.00-0.20
0.00-0.20

0.00-0.20

Data are presented as number (frequency); CI = 95% confidence interval.

from the control group. (MR = 2.27; 95% CI 1.95 to 2.64).

The mean MR showed a gene-dose effect: wt/wt = 2.75,
*4/wt = 2.05, *4/*4 = 0.698. The most rapid
metabolizers were from subjects who had the *xN genotype: MR = 2.76.
A multiple regression model was constructed to determine whether there was a significant association between the MR and a number of variables, such as genotype, age, gender, and number of relatives born in
Mexico. This analysis demonstrated a significant association of the MR with the *4 and *5 alleles (P < .05) but
not with any of the other variables.
DISCUSSION
There are relatively few pharmacogenetic studies of
Hispanics and only one other study of Mexican Americans examining phenotype and genotype characteris-

DEXTROMETHORPHAN METABOLISM IN MEXICAN AMERICANS

Figure 1. Histogram of log10 dextromethorphan/dextrorphan metabolic ratio (MR) in 50 Mexican American subjects.

tics of CYP2D6.11 The results of the present study demonstrated some similarities as well as differences from
other studies in Hispanics (Table IV). In the present report, 6% of the study group were poor metabolizers,
which is similar to the rate of 5% for Hispanics from
Spain.9 This finding is in contrast to a 3.2% poor
metabolizer rate for Mexican Americans in Los Angeles11 and a 3.6% poor metabolizer rate for Hispanics
in Nicaragua.10 The mean MR for extensive metabolizers
in this study (2.54) was similar to the mean MR found
for extensive metabolizers in Mexican Americans in
Los Angeles (2.47) and is similar to other studies in
whites.20-22

The *4 mutation of CYP2D6 is responsible for a reduced MR. In the present study, the frequency of the *4
allele was 0.17, which is significantly higher than that
reported by Mendoza et al11 in their study of Mexican
Americans in Los Angeles (P < .05). Hispanics in Nicaragua also had a higher *4 frequency of 0.16,10 whereas
Hispanics in Spain had *4 rates from 0.12 to 0.16.9,23
The frequencies of the *5 allele in these 4 studies are
generally similar, ranging from 0.02 to 0.04. The *10 allele, which is found in high frequency in Asian populations but in much lower frequency in white populations,1,5 was found in the present report with a frequency
of 0.01, whereas this mutation was found in Mexican
Americans in Los Angeles with a frequency of 0.07 (P <
.05). In the current report, the duplication gene which
is responsible for ultrarapid metabolism was found at a
frequency of 0.03, which is similar to the frequency for
Hispanics in Spain (0.03)8 but higher than that found
for Mexican Americans in Los Angeles (0.01). These
differences were not statistically different. It is interesting that the *17 mutation, which is rare in whites but
found more commonly in blacks,21,24 was found in 2 of
our patients (frequency, .02) but in much lower frequency in Mexican Americans in Los Angeles (frequency, 0.007; not significant; P > .05). The difference
in the poor metabolizer rate in the present study compared with that of Mexican Americans in Los Angeles
may be because of the different frequency of the *4 mutation, which was lower in Mexican Americans in Los
Angeles. As with other studies, the present study
showed that a gene-dose effect correlated with slowmetabolizing mutations (wt/wt = 2.75, *4/wt = 2.05,
*4/*4 = 0.698). All of the genotypic poor metabolizers
in the present study were identified by the established
antimode of greater than 0.3.25

Table IV Comparison of CYP2D6 Phenotype and Allelic Frequencies in Hispanics

PM, %

Present study
6.0 (1.3-16.5)
(Mexican
American)
Agundez et al
5.0 (2.1-7.2)
(Spain)8-10,16
Agundez et al
3.6 (1.2-8.3)
(Nicaragua)10
Mendoza et al
3.2 (1.4-6.2)
(Mexican
American)11

MR (EM)

*4

*5

*10

xN

2.54

0.17 (0.10-0.26)

0.02 (0.00-0.07)

0.01 (0.00-0.01)

0.03 (0.01-0.09)

0.06 (0.04-0.10)

0.03 (0.02-0.06)
0.01 (0.01-0.03)

0.12-0.16 (0.09-0.14) 0.02-0.04 (0.01-0.03)

0.16 (0.12-0.21)

0.04 (0.02-0.07)

0.03 (0.01-0.06)

2.47

0.10a (0.08-0.13)

0.02 (0.01-0.03)

0.07a (0.05-0.09) 0.01 (0.00-0.030)

95% confidence intervals are shown in brackets; PM = poor metabolizer; MR = metabolic ratio (mean); EM = extensive metabolizer.
a. Significantly different from present study, P < .05.

PHARMACOGENOMICS

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CASNER

The different frequencies of some genotypes found

in this study compared with that of Mendoza et al11
could be secondary to differences in the genetic
makeup of the 2 populations. For example, in the study
by Mendoza et al11 in Los Angeles, the requirement for
entry into the study was that each subject had to have at
least 3 of 4 grandparents of Mexican origin. This restriction was not used in the present study in
which Mexican American identity was based on selfidentification, which is recognized as a valid epidemiologic criterion.26,27 Subjects were asked about their
Mexican ancestry; the responses indicated that 64% of
our subjects had at least 4 relatives born in Mexico and
46% had both sets of grandparents as well as parents
born in Mexico. Nevertheless, it is possible that this
difference in our population sample could have
contributed to the difference in allele frequencies
found.
Mexicans are generally described as having contributions from 3 gene pools: Native American (31%),
Spanish European (61%), and African (8%).28-30 Mexican Americans are persons of Mexican ancestry living
in the Unites States, some of whose parents may have
intermarried with persons of non-Mexican ancestry. It
is interesting in this regard that 80% of the Mexican
Americans in the present study self-identify their race
as white, whereas only 10% identify themselves as
Mestizo. Of the Mexican Americans in the current
study, 68% were born in the United States and 32%
were born in Mexico. These demographics could be
construed to indicate a higher degree of intermarriage
with nonMexican American whites, which would
tend to increase the percentage of poor metabolizers as
well as the *4 allele compared with Mexican Americans
in Los Angeles.
Just as Hispanics in the United States are a heterogeneous population consisting of Mexican Americans,
Puerto Rican Americans, and Cuban Americans, there
is also heterogeneity within the Mexican American
population.31 For example, much of the Mexican
Americans of southern New Mexico and El Paso, Texas,
originated in northern Mexico, starting with Spanishspeaking settlers in the early 1600s, whereas the more
recent immigration from Mexico has come from deep
in the interior of the country.31 In addition, settlement
of Mexicans in California took place much later than
that of New Mexico and Texas.31 There are data to suggest that genetic admixture of the oldest generation in
Mexico exhibits the greatest Spanish influence, which
decreases in younger generations.32 These regional and
historical differences of immigration from Mexico

1234 J Clin Pharmacol 2005;45:1230-1235

could be the basis for different genetic admixture patterns.33 Finally, it is possible that some of the
differences found between this study and that of the
study of Mexican Americans in Los Angeles could be
attributable to differences of sample size. Sample size
in the present study was smaller than that in Los
Angeles. It is possible that with a larger sample size
some of the allele frequencies in the present study
could change.
In conclusion, the results of the present study suggest that for most of the drugs metabolized by the
CYP2D6 enzyme system, dosage adjustment would
only be required for a small percentage of Mexican
American patients. This is not to say that there are not
poor metabolizers in this population, because we
found that 6% of Mexican Americans will be poor
metabolizers, and these persons would be expected to
metabolize CYP2D6 drugs more slowly. A recent case
report described toxic effects of desipramine in Mexican Americans as a result of poor metabolizer CYP2D6
genotype.34 A larger study of Mexican Americans in the
El Paso region is planned to determine if some of the
observed differences in the CYP2D6 alleles of our subjects compared with those in the Los Angeles study are
because of genetic admixture or sampling differences.
This study was supported by a grant from the Center for Border
Health Research, El Paso, Texas. This study was presented in part as a
poster session at the 32nd annual meeting of the American College of
Clinical Pharmacology in Palm Harbor, Florida, September 21-23,
2003.

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