10.1177/0091270005280755DEXTROMETHORPHAN METABOLISM IN MEXICAN AMERICANSCASNERPHARMACOGENOMICS

The Effect of CYP2D6Polymorphisms on Dextromethorphan

Metabolism in Mexican Americans

Paul R. Casner, MD, PhD

A characteristic feature of drug action in individualpatients is the variability of drug metabolism from

one patient to another. This variability is related towell-known factors such as age, gender, environment,and genetics.1 Individual patients can be categorizedaccording to the rate of drug metabolism as either poormetabolizers, extensive metabolizers, and in some situ-ations, ultrarapid metabolizers.2 Minor alterations inthe amino acid makeup of a cytochrome P450 enzymemay result in altered metabolic activity. Severalcytochrome P450 enzymes exhibit a great deal of ge-netic polymorphisms. The CYP2D6 enzyme has morethan 80 alleles3 and is involved in the metabolism ofmore than 50 medications.4

About 5% to 10% of whites are poor metabolizers ofthe drugs that the CYP2D6 enzyme metabolizes be-

cause of specific mutations in the enzyme.5 Asians, onthe other hand, have very low rates of poor metabolizers(less than 1%).5 Some studies in blacks have shownthat up to 29% of studied populations are ultrarapidmetabolizers.6,7 Thus, it is apparent that there can be asignificant degree of genetic variation in the activity ofthe CYP2D6 enzyme, depending on the racial or ethnicmakeup of the population.1

There have been very few studies looking at the ac-tivity of CYP2D6 in Hispanics. Some of these studieswere performed in Hispanics of European origin, thatis, in Spaniards,8,9 and 1 study was performed in Nica-raguans.10 There is only 1 study describing CYP2D6 ge-notype and phenotype activity in Mexican Ameri-cans.11 The rapid growth of the Mexican Americanpopulation in the United States underscores the needfor continued studies that analyze drug-metabolizingcharacteristics of this minority population, which iscurrently the largest in the United States.12 The presentstudy examined the phenotypic and genotypic charac-teristics of CYP2D6 in Mexican Americans living in theborder region of El Paso, Texas.

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CYP2D6 is one of the most polymorphic of the cytochromeP450 enzymes. Genetic differences in this enzyme have beenreported in whites, blacks, and Asians. However, there is verylittle information about polymorphisms of this enzyme inMexican Americans. The objectives of the present study wereto assess the metabolic activity of CYP2D6 in a MexicanAmerican population using dextromethorphan and to corre-late this metabolic activity with a genotypic analysis. Thesample consisted of 50 Mexican American subjects and 25non–Mexican American controls. Overnight urine sampleswere collected and analyzed by high-performance liquidchromatography to calculate the metabolic ratio ofdextromethorphan to dextrorphan. Blood samples were col-

lected for genotypic analysis of CYP2D6 alleles. The fre-quency of the poor metabolizer phenotype was the same inthe Mexican American group and the non–Mexican Ameri-can group (6% vs 5.5%). The frequency of alleles in the Mexi-can American group was similar to frequencies published inother reports for non-Hispanic whites: *4 = 0.17, *5 = 0.02,*10 = 0.01, *17 = 0.02, *xN = 0.03. These results indicate thatcompared with non-Hispanic whites, Mexican Americanshave a similar proportion of poor metabolizer phenotype andsimilar genetic polymorphisms of CYP2D6.

Keywords: CYP2D6; pharmacogenetics; Mexican AmericanJournal of Clinical Pharmacology, 2005:45:1230-1235

©2005 the American College of Clinical Pharmacology

From the Department of Internal Medicine, Texas Tech University HealthSciences 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 UniversityHealth Sciences Center, El Paso, TX 79905.DOI: 10.1177/0091270005280755

METHODS

Subjects

A total of 75 subjects participated in this study. Thestudy group consisted of 50 Mexican American partici-pants and 25 non–Mexican American participants whoserved as controls. To qualify for the study, participantshad to be healthy, without any significant medicalproblems, nonsmokers, and without a history of alco-hol or drug use. A questionnaire was used to evaluatehealth status, medication use, and ethnic background.Patients were asked whether they considered them-selves to be Hispanic. Participants were also askedabout their country of birth, their race, and whethertheir parents and grandparents were born in Mexico.For the purposes of this study, participants were con-sidered to be Mexican American if they self-ratedthemselves as such. The demographic characteristicsof the patient sample are indicated in Table I. Thisstudy was approved by the Institutional Review Boardat the Texas Tech University Health Sciences Center, ElPaso campus.

Phenotyping

The dextromethorphan metabolic ratio (MR) was cal-culated as the ratio of the molar amount of the dextro-methorphan to that of dextrorphan in the urine after anovernight 8-hour collection. The dextromethorphanMR is reported as log10. Subjects were instructed toempty their bladder and then ingest 30 mg dextro-methorphan (Whitehall-Robbins, Madison, NJ). Pa-tients were instructed to transport the collected urinesample to the study center in a precooled cooler. Urinevolume was measured and aliquots of urine sampleswere stored at –70°C until assayed. Dextromethor-phan and dextrorphan levels were assayed by high-performance liquid chromatography analysis by a com-mercial laboratory (PPD Development, Middleton, Wis)according to the methodology of Bartoletti et al.13

Interassay coefficients of variation were 1.63% to2.29% for dextrorphan and 1.17% to 2.70% for dextro-methorphan. Intraassay coefficients of variation were1.1% to 8.4% for dextrorphan and were 2.84% to10.3% for dextromethorphan. The lower limit of detec-tion for dextrorphan was 0.1 µg/mL and 0.01 µg/mLfor dextromethorphan. The upper limit of detectionfor dextrorphan was 2.0 µg/mL and 2 µg/mL fordextromethorphan.

Genotyping

Ten milliliters of venous blood was collected from eachstudy participant. Blood was collected in tubes con-taining ethylenediamine tetraacetic acid, frozen andstored at –70°C until DNA extraction. A commerciallaboratory (PPGx Inc, Morrisville, NC) performed thegenotyping. The following alleles were assayed bypolymerase 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 de-scribed assay techniques.14 The *5 allele was analyzedby a long-range PCR method.15,16 The *xN allele was as-sayed by a long-range PCR method to amplify a 3.2kilobase product specific for the duplicated locus.17

The *10 and *17 alleles were identified by allele-specific assays according to Wang et al18 andMasimirembwa et al.19

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Table I Demographic Dataa

Mexican ControlAmerican (Non–Mexican American)

Age 36.5 ± 10.1b 42.9 ± 8.6Gender

Male 11 (22) 12 (48)Female 39 (78) 13 (52)

BirthplaceMexico 16 (32) 0United States 34 (68) 16 (64)Other 0 9 (36)

RaceWhite 40 (80) 18 (72)Asian 0 6 (24)Black 0 1 (4)Otherc 10 (20) 0

No. of relativesborn in Mexicod

6 23 (46)5 4 (8)4 5 (10)3 3 (6)2 6 (12)1 7 (14)0 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 aperson of mixed Spanish and Native American ancestry.d. Parents and grandparents (maternal and paternal).

Statistical Analysis

Statistical comparisons were made using the Student’st test and the Mann-Whitney U test. Allele frequencieswere compared using the Fisher’s exact test. To deter-mine contributing factors to the MR, a multiple regres-sion model was constructed using the MR as the de-pendent variable. Sample differences were consideredto be statistically significant for P < .05. Statistical anal-ysis was performed using a statistical software package(NCSS Statistical System for Windows, Kaysville,Utah).

RESULTS

Demographic data for the experimental and controlgroups are shown in Table I. The Mexican Americanstudy participants were younger than the non–Mexican American control group (P < .05). The Mexi-can American group had a higher percentage of females(78% vs 52%). The majority of Mexican Americanswere born in the United States (68%) as opposed toMexico (32%). Eighty percent considered themselveswhite. Approximately 65% of the Mexican Americangroup had at least 4 relatives (ie, parents or grandpar-ents) born in Mexico; 46% had both parents and bothsets of grandparents born in Mexico.

The allele frequencies for the Mexican Americangroup were similar to the white non–Mexican Ameri-can group and similar to established allele frequenciesfor whites (Table II). The *10 allele frequency in thecontrol group was significantly higher than in the Mex-ican American group. This finding is because 24% ofthe control group subjects identified themselves asAsian (Table I). There were 3 poor metabolizers in theMexican American group (two *4/*4, one *4/*5) and 1poor metabolizer in the non–Mexican American group(*4/*4). The *4 allele was the most common allele,with a frequency of 0.17. None of the Mexican Ameri-can subjects had *3, *6, *7, or *8. Genotype frequenciesare shown in Table III, with the most common variantgenotype being *4/wt.

The MR for dextromethorphan-dextrorphan wasable to separate the poor metabolizer by using the es-tablished antimode of the dextromethorphan-dextrorphan MR for whites (0.3, log10 = –0.53) (Figure1). The poor metabolizer frequency in the MexicanAmerican group was 6% versus 5.5% in the non–Mexican American group. The mean MR of the Mexi-can American group as a whole was –2.34 (95% confi-dence interval [CI] = –2.06 to –2.62), whereas the MR ofthe extensive metabolizers was –2.54 (95% CI = –2.35to –2.72). These values were not significantly different

fromthecontrolgroup.(MR=–2.27;95%CI–1.95to–2.64).The mean MR showed a gene-dose effect: wt/wt = –2.75,*4/wt = –2.05, *4/*4 = 0.698. The most rapidmetabolizers were from subjects who had the *xN ge-notype: MR = –2.76.

A multiple regression model was constructed to de-termine whether there was a significant association be-tween the MR and a number of variables, such as geno-type, age, gender, and number of relatives born inMexico. This analysis demonstrated a significant asso-ciation of the MR with the *4 and *5 alleles (P < .05) butnot with any of the other variables.

DISCUSSION

There are relatively few pharmacogenetic studies ofHispanics and only one other study of Mexican Ameri-cans examining phenotype and genotype characteris-

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Table II CYP2D6 Allele Frequencies

ControlMexican (Non–Mexican

American American)Allele n = 50 CI n = 25 CI

*4 17 (0.17) 0.10-0.26 9 (0.18) 0.09-0.31*5 2 (0.02) 0.00-0.070 1 (0.02) 0.00-0.11*10 1 (0.01)a 0.00-0.050 4 (0.08) 0.02-0.19*17 2 (0.02) 0.00-0.070 1 (0.02) 0.00-0.11*xN 3 (0.03) 0.01-0.09 1 (0.02) 0.00-0.11

Data are presented as number (frequency); CI = 95% confidence interval.a. Significantly different from control, P < .05.

Table III CYP2D6 Genotype Frequencies

ControlMexican (Non–Mexican

American American)Genotype n = 50 CI n = 25 CI

*4/wt 10 (0.20) 0.10-0.34 6 (0.24) 0.09-0.45*4/*4 2 (0.04) 0.01-0.14 1 (0.04) 0.00-0.20*4/*5 1 (0.02) 0.00-0.11 —*4/*10 — 1 (0.04) 0.00-0.20*5/wt 1 (0.02) 0.00-0.11 1 (0.04) 0.00-0.20*10/wt 1 (0.02) 0.00-0.11 1 (0.04) 0.00-0.20*10/*10 — 1 (0.04) 0.00-0.20*17/wt 2 (0.04) 0.01-0.14 —-*xN 1 (0.02) 0.00-0.11 —*xN/*4 2 (0.04) 0.01-0.14 —*xN/*17 — 1 (0.04) 0.00-0.20

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

tics of CYP2D6.11 The results of the present study dem-onstrated some similarities as well as differences fromother studies in Hispanics (Table IV). In the present re-port, 6% of the study group were poor metabolizers,which is similar to the rate of 5% for Hispanics fromSpain.9 This finding is in contrast to a 3.2% poormetabolizer rate for Mexican Americans in Los An-geles11 and a 3.6% poor metabolizer rate for Hispanicsin Nicaragua.10 The mean MR for extensive metabolizersin this study (–2.54) was similar to the mean MR foundfor extensive metabolizers in Mexican Americans inLos Angeles (–2.47) and is similar to other studies inwhites.20-22

The *4 mutation of CYP2D6 is responsible for a re-duced MR. In the present study, the frequency of the *4allele was 0.17, which is significantly higher than thatreported by Mendoza et al11 in their study of MexicanAmericans in Los Angeles (P < .05). Hispanics in Nica-ragua also had a higher *4 frequency of 0.16,10 whereasHispanics in Spain had *4 rates from 0.12 to 0.16.9,23

The frequencies of the *5 allele in these 4 studies aregenerally similar, ranging from 0.02 to 0.04. The *10 al-lele, which is found in high frequency in Asian popula-tions but in much lower frequency in white popula-tions,1,5 was found in the present report with a frequencyof 0.01, whereas this mutation was found in MexicanAmericans in Los Angeles with a frequency of 0.07 (P <.05). In the current report, the duplication gene whichis responsible for ultrarapid metabolism was found at afrequency of 0.03, which is similar to the frequency forHispanics in Spain (0.03)8 but higher than that foundfor Mexican Americans in Los Angeles (0.01). Thesedifferences were not statistically different. It is interest-ing that the *17 mutation, which is rare in whites butfound more commonly in blacks,21,24 was found in 2 ofour patients (frequency, .02) but in much lower fre-quency in Mexican Americans in Los Angeles (fre-quency, 0.007; not significant; P > .05). The differencein the poor metabolizer rate in the present study com-pared with that of Mexican Americans in Los Angelesmay be because of the different frequency of the *4 mu-tation, which was lower in Mexican Americans in LosAngeles. As with other studies, the present studyshowed that a gene-dose effect correlated with slow-metabolizing mutations (wt/wt = –2.75, *4/wt = – 2.05,*4/*4 = 0.698). All of the genotypic poor metabolizersin the present study were identified by the establishedantimode of greater than 0.3.25

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

Table IV Comparison of CYP2D6 Phenotype and Allelic Frequencies in Hispanics

PM, % MR (EM) *4 *5 *10 xN

Present study 6.0 (1.3-16.5) –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)(MexicanAmerican)

Agundez et al 5.0 (2.1-7.2) — 0.12-0.16 (0.09-0.14) 0.02-0.04 (0.01-0.03) 0.06 (0.04-0.10) 0.03 (0.02-0.06)(Spain)8-10,16

Agundez et al 3.6 (1.2-8.3) — 0.16 (0.12-0.21) 0.04 (0.02-0.07) 0.03 (0.01-0.06) 0.01 (0.01-0.03)(Nicaragua)10

Mendoza et al 3.2 (1.4-6.2) –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)(MexicanAmerican)11

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.

The different frequencies of some genotypes foundin this study compared with that of Mendoza et al11

could be secondary to differences in the geneticmakeup of the 2 populations. For example, in the studyby Mendoza et al11 in Los Angeles, the requirement forentry into the study was that each subject had to have atleast 3 of 4 grandparents of Mexican origin. This re-striction was not used in the present study inwhich Mexican American identity was based on self-identification, which is recognized as a valid epide-miologic criterion.26,27 Subjects were asked about theirMexican ancestry; the responses indicated that 64% ofour subjects had at least 4 relatives born in Mexico and46% had both sets of grandparents as well as parentsborn in Mexico. Nevertheless, it is possible that thisdifference in our population sample could havecontributed to the difference in allele frequenciesfound.

Mexicans are generally described as having contri-butions from 3 gene pools: Native American (31%),Spanish European (61%), and African (8%).28-30 Mexi-can Americans are persons of Mexican ancestry livingin the Unites States, some of whose parents may haveintermarried with persons of non-Mexican ancestry. Itis interesting in this regard that 80% of the MexicanAmericans in the present study self-identify their raceas white, whereas only 10% identify themselves asMestizo. Of the Mexican Americans in the currentstudy, 68% were born in the United States and 32%were born in Mexico. These demographics could beconstrued to indicate a higher degree of intermarriagewith non–Mexican American whites, which wouldtend to increase the percentage of poor metabolizers aswell as the *4 allele compared with Mexican Americansin Los Angeles.

Just as Hispanics in the United States are a heteroge-neous population consisting of Mexican Americans,Puerto Rican Americans, and Cuban Americans, thereis also heterogeneity within the Mexican Americanpopulation.31 For example, much of the MexicanAmericans of southern New Mexico and El Paso, Texas,originated in northern Mexico, starting with Spanish-speaking settlers in the early 1600s, whereas the morerecent immigration from Mexico has come from deepin the interior of the country.31 In addition, settlementof Mexicans in California took place much later thanthat of New Mexico and Texas.31 There are data to sug-gest that genetic admixture of the oldest generation inMexico exhibits the greatest Spanish influence, whichdecreases in younger generations.32 These regional andhistorical differences of immigration from Mexico

could be the basis for different genetic admixture pat-terns.33 Finally, it is possible that some of thedifferences found between this study and that of thestudy of Mexican Americans in Los Angeles could beattributable to differences of sample size. Sample sizein the present study was smaller than that in LosAngeles. It is possible that with a larger sample sizesome of the allele frequencies in the present studycould change.

In conclusion, the results of the present study sug-gest that for most of the drugs metabolized by theCYP2D6 enzyme system, dosage adjustment wouldonly be required for a small percentage of MexicanAmerican patients. This is not to say that there are notpoor metabolizers in this population, because wefound that 6% of Mexican Americans will be poormetabolizers, and these persons would be expected tometabolize CYP2D6 drugs more slowly. A recent casereport described toxic effects of desipramine in Mexi-can Americans as a result of poor metabolizer CYP2D6genotype.34 A larger study of Mexican Americans in theEl Paso region is planned to determine if some of theobserved differences in the CYP2D6 alleles of our sub-jects compared with those in the Los Angeles study arebecause of genetic admixture or sampling differences.

This study was supported by a grant from the Center for BorderHealth Research, El Paso, Texas. This study was presented in part as aposter session at the 32nd annual meeting of the American College ofClinical Pharmacology in Palm Harbor, Florida, September 21-23,2003.

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