Clinical Chemistry AACC Online Job Center
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Clinical Chemistry 46: 18-23, 2000;
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow A correction has been published
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (42)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Garcia-Barceló, M.
Right arrow Articles by Waye, M. M. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Garcia-Barceló, M.
Right arrow Articles by Waye, M. M. Y.
Related Collections
Right arrow Molecular Diagnostics and Genetics
(Clinical Chemistry. 2000;46:18-23.)
© 2000 American Association for Clinical Chemistry, Inc.

Articles

Genetic Analysis of the CYP2D6 Locus in a Hong Kong Chinese Population

Mercè Garcia-Barceló1,a, Lok Yee Chow1, Helen Fung Kum Chiu1, Yun Kowk Wing1, Dominic Tak Shing Lee1, Kwok Lim Lam1 and Mary Miu Yee Waye2

1 Department of Psychiatry, 11/F Room 134046, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

2 Department of Biochemistry, Room 608, 6/F Mong Man Wai Building, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
a Author for correspondence. Fax 852-2646-2284; e-mail b025744{at}mailserv.cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Background: The cytochrome P450 CYP2D6 enzyme debrisoquine 4-hydroxylase metabolizes many different classes of commonly used drugs, such as tricyclic antidepressants and neuroleptics. Genetic polymorphism of the CYP2D6 gene is responsible for pronounced interindividual and interracial differences in the metabolism of these drugs. The CYP2D6*10 allele and its variants are the most frequent alleles found in Orientals, and they are responsible for diminished debrisoquine 4-hydroxylase activity because of the presence of a C188->T mutation in exon 1.

Methods: One hundred nineteen Hong Kong Chinese subjects were genotyped by means of allele-specific PCR, PCR, and restriction enzyme analysis for 10 CYP2D6 alleles (CYP2D6*1, *2, *4D, *5, *8/*14, *10A, *10B, *15, *16, and J9).

Results: CYP2D6*10B was the most prevalent allele, and CYP2D6*10/CYP2D6*10 was the most frequent genotype, representing 46.22% of the population.

Conclusions: There was no significant difference in the prevalence of the alleles analyzed between our study and the Chinese populations genotyped previously. This is the largest study in terms of the number of CYP2D6 alleles analyzed in an Oriental population and the first one conducted in a Hong Kong Chinese population.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Debrisoquine-4-hydroxylase, a cytochrome P450 enzyme known as CYP2D6 enzyme, metabolizes different types of pharmacotherapeutic drugs, such as tricyclic antidepressants and neuroleptics. The gene encoding for CYP2D6 enzyme, CYP2D6, is part of a cluster on chromosome 22 that includes two to three related pseudogenes (1). Starting at the 5' end of the cluster, there are two nonfunctional pseudogenes, CYP2D8P and CYP2D7AP (an additional pseudogene CYP2D7BP can also be found), followed by the active gene, CYP2D6. Several mutated alleles of the CYP2D6 locus have been identified and associated with alterations in the metabolism of debrisoquine and related drugs. Consequently, the activity of the CYP2D6 enzyme ranges from ultrarapid (ultrarapid metabolizer) to a complete absence [poor metabolizer (PM)].1 Individuals homozygous or heterozygous for deficient CYP2D6 alleles metabolize drugs at lower rates, which leads to an increased risk of side effects and drug toxicity. On the other hand, individuals with duplication of either the active gene CYP2D6 or the CYP2D62 allele metabolize drugs at ultrarapid rate, which may lead to therapeutic failure.

In addition to interindividual variability in CYP2D6 enzyme activity, the incidence of PMs of debrisoquine has been shown to vary between different populations. The prevalence of PMs ranges from <1% in some Oriental populations to as high as 19% in some black populations (2). In particular, differences between Caucasian and Oriental populations have been studied exhaustively (3)(4)(5)(6)(7)(8). Interracial differences are explained by an unequal distribution of the alleles of the CYP2D6 gene among different populations. The defective alleles CYP2D63 and CYP2D64 that give rise to the PM phenotype in Caucasians are rarely found in Chinese, explaining the low frequency of PMs in this population. However, these two races differ not only in the incidence of PMs but also in the activity of debrisoquine hydroxylase within the extensive metabolizer (EM) phenotype. The distribution of the debrisoquine metabolic ratios is shifted toward higher values among Chinese EMs, indicating lower CYP2D6 enzyme activity. These individuals are classified as intermediate metabolizers. The lower enzyme activity in Oriental EMs is associated with the frequent presence of the allele CYP2D10 and its variants, CYP2D10A and CYP2D10B. These alleles contain a C188->T mutation that causes a Pro34->Ser amino acid substitution, leading to the formation of an unstable enzyme with lower metabolic activity (3).

Earlier studies have indicated that there may be differences in CYP2D6 enzyme activity not only between the major races but also among different Oriental populations (4)(5)(6)(7)(8). Consequently, further studies on different Oriental ethnic groups were urgently needed to provide important genotypic data for facilitating rational therapeutics. In this study, we analyzed the molecular basis of the CYP2D6 polymorphism in a Hong Kong Chinese population, aiming at characterizing the distribution of known alleles of the CYP2D6 locus. The genotyping analysis presented here comprises the identification of 10 CYP2D6 alleles (including the wild type) by PCR-based methods (Table 1 ). CYP2D6 alleles are designated according to the current nomenclature (9).


View this table:
[in this window]
[in a new window]
  		Table 1. Analysis of the mutations and identification of CYP2D6 alleles by PCR-based methods.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
individuals
One hundred nineteen unrelated Chinese individuals participated in the genotyping tests after giving their informed consent. The subjects include 70 healthy volun-teers and 49 patients diagnosed with depressive illness according to DSM IV (10). This research project was approved by the local ethics committee.

statistics
The frequency of a determined CYP2D6X allele in a sample of N individuals was estimated by (2nx/x + nx/-)/2N, where nx/x is the number of individuals homozygous for X, and nx/- is the number of individuals heterozygous for the X allele. Allele frequencies in different populations were compared using Z-test for proportions.

genotype determination
Blood samples (12 mL) were collected in Vacutte® (Greiner) tubes containing EDTA as an anticoagulant. DNA was extracted using a QIAamp blood kit (Qiagen). PCR followed by either restriction-enzyme digestion of the amplified product or allele-specific PCR (ASPCR) tests was used to identify some of the CYP2D6 alleles. The mutations analyzed for each of the alleles and primers and/or enzymes used for the corresponding tests are summarized in Table 1Up . Sequences and locations of the primers for each PCR/ASPCR reaction are specified in Table 2 .


View this table:
[in this window]
[in a new window]
  		Table 2. Sequences and locations of primers used in PCR reactions.

The first step was the amplification of a 5093-bp genomic DNA fragment, containing all nine CYP2D6 exons, to be used as an amplicon for the subsequent PCR-based tests. Genomic DNA (400 ng) was used as template and the Expand Long Template PCR SystemTM (Boehringer) was applied. The reaction was carried out in a 25-µL mixture containing buffer 3 (supplied with the kit), 2.5 mmol/L MgCl2, 500 µmol/L deoxynucleotide triphosphates, 0.5 µmol/L of each of the CYP2D6-specific primers (2D6F and 2D6R; see Table 2Up ) and 2 U of the enzyme mixture (Taq and Pwo polymerases). The cycle profile was as follows: predenaturation at 94 °C for 2 min, followed by 10 cycles of denaturation at 94 °C for 1 min, annealing at 60 °C for 30 s, and synthesis at 68 °C for 4 min. These 10 cycles were followed by 30 additional cycles in which the elongation time was increased by 20 s in each cycle. The final elongation step was 7 min at 68 °C. Approximately 10 ng of the 5093-bp PCR product was used as a template in the subsequent nested PCR reactions. Detection of the mutations was performed as per the corresponding references listed in Table 1Up . Only the modifications and/or new assays are described in this report. All PCR reactions were carried out in a PTC-200 DNA Engine thermocycler (MJ Research) or in a Mastercycler Gradient thermocycler (Eppendorf). PCR products were detected in ethidium bromide-agarose gels.

frequency of the c188->t mutation
Additional precautions to increase specificity were taken when checking for mutations in exon 1 and 2, especially for the mutation C188->T, which is responsible for decreased CYP2D6 enzyme activity in Orientals (3)(6). To exclude any possible artifact attributable to the coamplification of CYP2D7P, primer M, whose sequence is unique to CYP2D6, was used in combination with primer A to amplify exons 1 and 2 of the active gene. PCR was carried out using the same cycling conditions as those to amplify the whole gene. The concentrations of MgCl2 and the primers were 2.5 mmol/L and 0.4 µmol/L, respectively. The 1193-bp PCR product (amplicon AM) was used as a template for the subsequent rounds of PCR reactions to allow detection of mutations in introns 1 and 2. For C188->T, primers A and B were used. A parallel PCR reaction using primers A and 10B was carried out to detect the CYP2D7P-derived sequence in the region 302–333, characteristic of CYP2D62, and to rule out any possible misinterpretation of C188->T (3). The final concentrations of the PCR reagents for a 25-µL reaction were as follows: 0.8 mmol/L MgCl2, 40 µmol/L dNTPs, 0.250 µmol/L of each primer, and 0.5 U of the Taq polymerase enzyme (Boehringer Mannheim). The cycle profile was as follows: predenaturation at 94 °C for 2 min, followed by 25 cycles of denaturation at 94 °C for 1 min, annealing at 66 °C for 30 s, and synthesis at 72 °C for 1.5 min. The final elongation step was 7 min at 72 °C. The PCR products obtained, which were 270 bp when A and B were used for amplification and 230 bp when A and 10B were used, were digested by HphI as described previously (6).

frequency of the t226 insertion mutation
In CYP2D8P and CYP2D7P pseudogenes, a T exists at the 226 site corresponding to exon 1 of the wild-type CYP2D6 gene (11)(12). Hence, to exclude artifacts caused by coamplification of pseudogenes, amplicon AM was used as a template for subsequent reactions. PCR products generated by the primer pairs A and B (270 bp) and A and 10B (230 bp) were digested by BspMI (11).

frequency of the c1127->t mutation
The mutation C1127->T was checked by amplifying 10 ng of amplicon AM with allele-specific primers 1127W and 1127A, and the reverse primer M. The final concentrations of the PCR reagents were as follows: 0.8 mmol/L MgCl2, 40 µmol/L dNTPs, 0.200 µmol/L of each primer, and 0.25 U of Taq polymerase (Boehringer Mannheim). Cycling conditions were as follows: predenaturation at 97 °C for 2 min, followed by 25 cycles of denaturation at 94 °C for 1 min, annealing at 62 °C for 30 s, and synthesis at 72 °C for 1 min. The final elongation step was 7 min at 72 °C.

frequency of the g1749->c mutation
ASPCR by competitive oligonucleotide priming (13) was used for the detection of this mutation. The previously amplified CYP2D6 gene was used as a template in a PCR reaction buffer similar to that described above for C188->T. Primers E, F, and 1749W or 1749A (for the parallel reaction) were used. Cycling conditions were as follows: predenaturation at 97 °C for 2 min, followed by 20 cycles of denaturation at 94 °C for 1 min, annealing at 66 °C for 30 s, and synthesis at 72 °C for 1 min. The final elongation step was 7 min at 72 °C.

frequency of the cyp2d65 allele
The deletion allele CYP2D65 was identified using primers Z and Y, which are located in CYP2D7 and in the 3'-flanking region of CYP2D6, respectively (Table 2Up ). We applied the method described by Griese et al. (14) with some modifications. PCR was performed on a PTC-200 DNA Engine thermocycler using the Expand Long Template PCR System. The reaction was carried out in a 25-µL mixture containing buffer 3 (supplied with the kit), MgCl2 at 2.25 mmol/L, deoxynucleotide triphosphates at 500 µmol/L each, each of the primers at 0.3 µmol/L, and 500 ng of genomic DNA as template. The cycle profile was as follows: predenaturation at 93 °C for 1 min, followed by 39 cycles of denaturation at 93 °C for 1 min, annealing at 63 °C for 30 s, and synthesis at 68 °C for 6 min. The final elongation step was 7 min at 72 °C. Carriers of allele 5 revealed a 6.2-kb PCR fragment amplification. This assay was validated using as a positive control a DNA sample from an individual showing (by Southern blot) a XbaI 11.5-kb restriction fragment indicative of CYP2D5 (gift from Dr. J. M. Agúndez, Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain). Detection of the CYP2D65 allele was submitted to different PCR tests to confirm the results. To this end, primer Y was used in combination with primer CYP13 under the same PCR conditions. This assay yielded a 3.5-kb fragment (15).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
cyp2d6 alleles
DNA from all individuals was analyzed for most key mutations as described by Daly et al. (9) (see Table 1Up ). The frequencies of the CYP2D6 alleles investigated in this study are listed in Table 3 , and a comparison with the CYP2D6 frequencies found in other studies conducted in Chinese populations is presented in Table 4 . We found 5 known alleles out of 10 CYP2D6 alleles analyzed. Our genotype results are generally in agreement with the published sequences at the investigated target sites. Each of the CYP2D62 alleles contained the CYP2D7-derived sequence in the region 302–333 in intron 1. However, the converted intronic sequence was also found in two CYP2D61 alleles (wild type). In addition, one individual presented an 2 allele with an additional C1127->T mutation, a variant described previously (16), and two other individuals presented 2 alleles without mutation C2938->T. On the other hand, two individuals homozygous for the CYP2D610 alleles were found to have mutation C2938->T, which is characteristic of allele 2. The presence of this particular mutation, which causes an Arg296->Cys amino acid substitution, can be considered of high functional importance as exemplified by its significant role in the CYP2D617 allele (17). Further studies on alterations of the enzymatic activity caused by the combinations of these mutations are on going. The frequency of allele 2 was somewhat lower than that found in previous studies conducted in Chinese populations (Table 4 ) (7). As for CYP2D610 alleles, the frequencies were 10.51% for the variant 10A and 54.20% for the variant 10B. The CYP2D610C allele was not analyzed because it is present together with the 10B allele in Oriental subjects with a 44-kb XbaI haplotype (3)(8). The prevalence of mutation C188->T, which is characteristic of the 10 alleles, was 64.71%. As shown in Table 4 , the frequency of C188->T was higher than that found in Chinese living in Sweden (51%) (3)(7) and similar to that found in Taiwanese Chinese (70%) and Chinese living in Singapore (62%) (6)(18). These differences in the frequency of C188->T were not statistically significant and could be attributed to the different methods applied for its detection (3).


View this table:
[in this window]
[in a new window]
  		Table 3. Frequencies of the CYP2D6 alleles identified in the present study.


View this table:
[in this window]
[in a new window]
  		Table 4. Frequencies of CYP2D6 alleles found in Chinese populations.

Alleles CYP2D615 (11), CYP2D616 (12), and CYP2D68/14 (19)(20) seem to be very rare mutant alleles in Caucasians as well as in Orientals. To date, no studies on their prevalence have been done in Oriental populations, and our results show that alleles 15 and 16 are rare in these population. Recently, three 14 alleles were characterized in a sample of 124 (1.2%) Taiwanese Chinese subjects by Wang et al. (20).

As expected, CYP2D64D, which is the main allele responsible for the PM phenotype in Caucasians (21), was not detected in our study.

CYP2DJ9 was first detected in Japanese (22)(23) with a very low frequency (0.7%). Because of the similarity between the Japanese and Chinese populations, we thought it would be of interest to find the distribution of CYP2DJ9 in Chinese because it has not been studied previously. However, this allele was not found in the Hong Kong population studied.

cyp2d6 genotypes
We found eight different genotypes, which are listed together with their respective frequencies in Table 5 . As expected, the most frequent genotype was 10/10, followed by 1/10. Individuals homozygous for allele 10 have impaired metabolism of debrisoquine-4-hydroxylase, which explains the right shift in the metabolic ratio of debrisoquine among Chinese when compared with Caucasian EMs.


View this table:
[in this window]
[in a new window]
  		Table 5. Frequency of CYP2D6genotypes.

No significant differences in allele distribution or genotype were observed between psychiatric patients and healthy individuals. However, it is worth mentioning that psychiatric patients showed a higher frequency overall of allele 2 when compared with the controls (data not shown). This observation requires further study because discrepancies in the of catalytic activity of allele 2 have been reported (24). In addition, allele 2 is the main CYP2D6 variant behind the genetic mechanism that originates duplications of the active CYP2D6 gene that gives rise to the ultrarapid metabolizer phenotype (25)(26). Thus, there may be clinical relevance for the drug treatment of psychiatric patients harboring this allele.

In Orientals, PCR-based detection of the 10/10 genotype should be recommended when CYP2D6-metabolized drugs are applied.


   Footnotes
 
1 Nonstandard abbreviations: PM, poor metabolizer; EM, extensive metabolizer; and ASPCR, allele-specific PCR.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez F. The human debrisoquine 4-hydroxylase (CYP2D6) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene and a pseudogene. Am J Hum Genet 1989;45:889-904. [ISI][Medline] [Order article via Infotrieve]
  2. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Clin Pharmacokinet 1995;29:192-209. [ISI][Medline] [Order article via Infotrieve]
  3. Johansson I, Oscarsson M, Yue Q-Y, Bertilsson L, Sjövist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P450 locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452-459. [Abstract]
  4. Horai Y, Nakano M, Ishizaki T, Ishikawa K, Zhou H-H, Zhou B-J, et al. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther 1989;46:198-207. [ISI][Medline] [Order article via Infotrieve]
  5. Sohn D-R, Shin S-G, Park C-W, Kusaka M, Chiba K, Ishizaki T. Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Br J Clin Pharmacol 1991;32:504-507. [ISI][Medline] [Order article via Infotrieve]
  6. Wang SL, Huang JD, Lai MD, Liu BH, Lai ML. Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6. Clin Pharmacol Ther 1993;53:410-418. [ISI][Medline] [Order article via Infotrieve]
  7. Dahl M-L, Yue Q-Y, Roh H-K, Johansson S, I, äwe J, Sjövist F, Bertilsson L. Genetic analysis of the CYP2D6 locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects. Pharmacogenetics 1995;5:159-164. [ISI][Medline] [Order article via Infotrieve]
  8. Roh H-K, Dahl M-L, Johansson I, Ingelman-Sundberg M, Cha Y-M, Bertilsson L. Debrisoquine and S-mephenytoin hydroxylation phenotypes and genotypes in a Korean population. Pharmacogenetics 1996;6:441-447. [ISI][Medline] [Order article via Infotrieve]
  9. Daly AK, Brockmöller J, Broly F, Eichelbaum M, Evans WE, Gonzalez FJ, et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 1996;6:193-201. [ISI][Medline] [Order article via Infotrieve]
  10. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994:317–92..
  11. Sachse C, Brockmöller J, Bauer S, Reum T, Roots I. A rare insertion of T226 in exon 1 of CYP2D6 causes a frameshift and is associated with the poor metabolizer phenotype: CYP2D6*15. Pharmacogenetics 1996;6:269-272. [ISI][Medline] [Order article via Infotrieve]
  12. Daly AK, Fairbrother KS, Andreassen OA, London SJ, Idle JR, Steen VM. Characterization and PCR based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype. Pharmacogenetics 1996;6:319-328. [ISI][Medline] [Order article via Infotrieve]
  13. Bottema CDK, Sommer SS. PCR amplification of specific alleles: Rapid detection of known mutations and polymorphism. Mutat Res 1993;288:93-102. [ISI][Medline] [Order article via Infotrieve]
  14. Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Mörike K, et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 1998;8:15-26. [ISI][Medline] [Order article via Infotrieve]
  15. Daly AK, Steen VM, Fairbrother KS, Idle JR. CYP2D6 multiallelism. Methods Enzymol 1996;272:199-210. [ISI][Medline] [Order article via Infotrieve]
  16. Marez D, Legrand M, Sabbaagh N, Lo Guidice JM, Spire C, Lafitte JJ, et al. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 1997;7:193-202. [ISI][Medline] [Order article via Infotrieve]
  17. Oscarson M, Hidestrand M, Johansson I, Ingelman-Sundberg M. A combination of mutations in the CYP2D*17 (CYP2D6Z) allele causes alterations in enzyme function. Mol Pharmacol 1997;52:1034-1040. [Abstract/Free Full Text]
  18. Lee EJD, Jeyaseelan K. Frequency of human CYP2D6 mutant alleles in a normal Chinese population. Br J Clin Pharmacol 1994;37:605-607. [ISI][Medline] [Order article via Infotrieve]
  19. Broly F, Marez D, Sabbaagh N, Legrand M, Millecamps S, Lo Guidice JM, et al. An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis. Pharmacogenetics 1995;5:373-384. [ISI][Medline] [Order article via Infotrieve]
  20. Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos 1999;27:385-388. [Abstract/Free Full Text]
  21. Heim HH, Meyer UA. Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification. Lancet 1990;336:529-532. [ISI][Medline] [Order article via Infotrieve]
  22. Yokoi T, Kosaka Y, Chida M, Chiba K, Nakamura H, Ishizaki T, et al. A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype. Pharmacogenetics 1996;5:395-441.
  23. Yokoi T, Kamataki T. Genetic polymorphism of drug metabolizing enzymes: new mutations in CYP2D6 and CYP2A6 genes in Japanese. Pharmacol Res 1998;15:517-524.
  24. Sachse C, Brockmöller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997;60:284-295. [ISI][Medline] [Order article via Infotrieve]
  25. Johansson I, Lundqvist E, Bertilsson L, Dahl M-L, Sjövist F, Ingelman-Sundberg M. Inherited amplification of an active gene in the cytochrome P450 CYP2D6 locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci U S A 1993;90:11825-11829. [Abstract/Free Full Text]
  26. Lundqvist E, Johansson J, Ingelman-Sundberg M. Genetic mechanisms for duplication and multiplication of the human CYP2D6 gene and methods for detection of duplicated CYP2D6 genes. Gene 1999;226:327-338. [ISI][Medline] [Order article via Infotrieve]
  27. Wang SL, Lai MD, Lai ML, Huang JD. R296C and other CYP2D6 mutations in Chinese. Pharmacogenetics 1995;5:385-388. [ISI][Medline] [Order article via Infotrieve]
  28. Chen S, Chou W-H, Blouin RA, Mao Z, Humphries LL, Meek QC, et al. The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence in clinical outcomes in psychiatry. Clin Pharm Ther 1996;5:522-534.



The following articles in journals at HighWire Press have cited this article:


Home page
 Ann OncolHome page
Y. Xu, Y. Sun, L. Yao, L. Shi, Y. Wu, T. Ouyang, J. Li, T. Wang, Z. Fan, T. Fan, et al.
Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment
Ann. Onc., August 1, 2008; 19(8): 1423 - 1429.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
B. M. Johnson, I. H. Song, K. K. Adkison, J. Borland, L. Fang, Y. Lou, M. M. Berrey, A. N. Nafziger, S. C. Piscitelli, and J. S. Bertino Jr
Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail.
J. Clin. Pharmacol., May 1, 2006; 46(5): 577 - 587.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
S. Bernard, K. A. Neville, A. T. Nguyen, and D. A. Flockhart
Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications.
Oncologist, February 1, 2006; 11(2): 126 - 135.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
O. Q. P. Yin, X. J. Shi, B. Tomlinson, and M. S. S. Chow
EFFECT OF CYP2D6*10 ALLELE ON THE PHARMACOKINETICS OF LORATADINE IN CHINESE SUBJECTS
Drug Metab. Dispos., September 1, 2005; 33(9): 1283 - 1287.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. Yu, B. M. Kneller, A. E. Rettie, and R. L. Haining
Expression, Purification, Biochemical Characterization, and Comparative Function of Human Cytochrome P450 2D6.1, 2D6.2, 2D6.10, and 2D6.17 Allelic Isoforms
J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1291 - 1300.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
L. Ji, S. Pan, J. Marti-Jaun, E. Hanseler, K. Rentsch, and M. Hersberger
Single-Step Assays to Analyze CYP2D6 Gene Polymorphisms in Asians: Allele Frequencies and a Novel *14B Allele in Mainland Chinese
Clin. Chem., July 1, 2002; 48(7): 983 - 988.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
R. Siebers
Data Inconsistencies in Abstracts of Articles in Clinical Chemistry
Clin. Chem., January 1, 2001; 47(1): 149 - 149.
[Full Text] [PDF]

Home page
 Clin. Chem.Home page
M. Garcia-Barcelo, L. Y. Chow, K. L. Lam, H. F. K. Chiu, Y. K. Wing, and M. M. Y. Waye
Occurrence of CYP2D6 Gene Duplication in Hong Kong Chinese
Clin. Chem., September 1, 2000; 46(9): 1411 - 1413.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow A correction has been published
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (42)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Garcia-Barceló, M.
Right arrow Articles by Waye, M. M. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Garcia-Barceló, M.
Right arrow Articles by Waye, M. M. Y.
Related Collections
Right arrow Molecular Diagnostics and Genetics

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS