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Drug Metab. Pharmacokinet. 27 (1): 5567 (2012). Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) Review Pharmacogenomics of CYP2D6: Molecular Genetics, Interethnic Differences and Clinical Importance Lay Kek T EH 1, * and Leif B ERTILSSON 2 1 Pharmacogenomics Centre (PROMISE), Faculty of Pharmacy, Universiti Teknologi MARA, Malaysia 2 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University, Hospital-Huddinge, Karolinska Institutet, Stockholm, Sweden Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: CYP2D6 has received intense attention since the beginning of the pharmacogenetic era in the 1970s. This is because of its involvement in the metabolism of more than 25% of the marketed drugs, the large geographical and inter-ethnic differences in the genetic polymorphism and possible drug-induced toxicity. Many interesting reviews have been published on CYP2D6 and this review aims to reinstate the importance of the genetic polymorphism of CYP2D6 in different populations as well as some clinical implications and important drug interactions. Keywords: CYP2D6 polymorphism; interethnic differences; clinical implication CYP2D6 gene resulting in amino acid substitutions, which alter catalytic activity, enzyme stability, and/or substrate specificity. The CYP2D6 gene is localized on chromosome 22q13.1. It contains 9 exons11¥ within 4,383 bp based on the NCBI 37 genome assembly. The evolution of the human CYP2D locus has involved elimination of three genes and inactivation of two neighbouring genes ¤CYP2D7 and CYP2D8P¥ and partial inactivation of one CYP2D6. These genes display 92®97% nucleotide similarity across their introns and exons. The CYP2D8P gene was found to be a pseudogene and to contain several gene-disrupting insertions, deletions, and termination codons within its exons. CYP2D7, which is just downstream of CYP2D8P, is apparently normal, except for the presence, in the first exon, of an insertion that disrupts the reading frame. These two closely related genes were believed to transfer detrimental mutations via gene conversions into the CYP2D6 gene and were hypothesised to account for the high prevalence of variants which most commonly encode defective gene products. A combination of polymorphisms, including SNPs, duplications, insertion/deletions and/or gene conversions, have been reported to cause increased or reduced CYP2D6 enzyme activity. These alleles include 7 normal or increased activity alleles ª*1,11,12¥ *2,12®17¥ *27,12,15¥ *33,12¥ *35,12,18,19¥ *48,15,20¥ *5315,21¥«, 11 alleles with reduced activity ª*9,22¥ CYP2D6 Genetic Polymorphism Cytochrome P450 ¤CYP¥ 2D6 is one of the most widely investigated CYPs in relation to genetic polymorphism. Typical substrates for CYP2D6 are largely lipophilic in nature and include antidepressants, antipsychotics, antiarrhythmics, antiemetics, beta-adrenoceptor antagonists ¤beta-blockers¥ and opioids, which represent approximately 25% of currently marketed drugs.1®3¥ The enzyme is largely non-inducible and represents 1®5% of the total P450 in the liver.4®6¥ One of the reasons for the large research interest of this enzyme is the wide inter-individual variation in the enzyme activity of CYP2D which led to discovery of deletion and duplication of the CYP2D6 gene. In addition, the discovery of CYP2D6 polymorphism7®9¥ has created new interest in the role of pharmacogenetics in clinical pharmacology since the 1970s. Molecular Genetics of CYP2D6 CYP2D6 is the only functional gene in the CYP2D subfamily of the human genome.10¥ To date, more than 80 allelic variants have been reported for CYP2D6 ¤http: //www.imm.ki.se/cypalleles/cyp2d6.htm¥. The most common functional polymorphism in drug metabolizing enzymes ¤DMEs¥ is point mutations in coding regions of the Received October 9, 2011; Accepted December 6, 2011 J-STAGE Advance Published Date: December 20, 2011, doi:10.2133/dmpk.DMPK-11-RV-121 *To whom correspondence should be addressed: Lay Kek TEH, Ph.D., Pharmacogenomics Centre (PROMISE), Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Puncak Alam, Selangor DE, Malaysia. Tel. +603-32584685, Fax. +603-32584602, E-mail: tehlaykek@puncakalam. uitm.edu.my/[email protected] 55 56 Lay Kek TEH and Leif BERTILSSON *10,12,15,23®27¥ *17,28,29¥ *29,12,30¥ *41,31®33¥ *49,15,20,34¥ *50,15,20¥ *54 & *55,15,21¥ *59,12,33¥ *7234¥«, 26 nonfunctional alleles ª*3,12,35¥ *4,12,16,35®41¥ *5,42,43¥ *6,12,44®46¥ *7,45¥ *8,47¥ *11,48¥ *12,49¥ *13,19,50®52¥ *14,15,26,53¥ *15,54¥ *16,51,52¥ *18,15,55¥ *19,12¥ *20,56¥ *21,12,57,58¥ *31,12,50,59¥ 15,25,41,60¥ 60¥ 61¥ 62¥ 58¥ *36, *38, *40, *42, *44, *47 & *51,15,20¥ 63,64¥ 65¥ *56, *62 «, and many functionally undetermined alleles ª*22®*26, *28, *30, *32, *34, *37,12¥ *39,15,39¥ *43,12¥ *45 & *46,17¥ *52,66¥ *68,67¥ *70,68¥ *71,69¥ *73 & *74,70¥ *75,71¥ *8272¥«. In addition, copy number variations ¤CNVs¥ of the normal, nonfunctional, and reduced activity CYP2D6 alleles are observed, and these have been associated with variation of in vivo CYP2D6 enzyme activity. For example, more than two copies of CYP2D6 normal alleles e.g., ª*1 ' N,16¥ *2 ' N,13,73,74¥ *35 ' N,75¥ 13 h N h 2¥« have been shown to elevate CYP2D6 enzyme activity. Individuals who inherit these alleles are ultra-rapid metabolisers ¤UMs¥ of CYP2D6. CNVs are also found for nonfunctional ª*4 ' N,43,76,77¥ *36 ' N15,25,41,60¥« and reduced activity alleles ª*10 ' N27,53,78,79¥«, *17 ' N,80¥ *9 ' N81¥«, but individuals who inherit these alleles do not have increased metabolism of CYP2D6 substrates. In contrast to gaining extra copies of the CYP2D6 gene, CYP2D6*5 is a loss of gene copy that produces no CYP2D6 protein.42¥ Individuals with two nonfunctional CYP2D6 alleles, including CYP2D6*5, have no CYP2D6 activity, and are classified as poor metabolisers ¤PMs¥. It is noteworthy that CYP2D6*36, which has negligible activity, exists on each chromosome in three forms: ¤i¥ CYP2D6*36 ' 2 ¤two copies of a nonfunctional allele¥; ¤ii¥ CYP2D6*36¦*10 ¤one copy of a nonfunctional allele in a tandem arrangement with *10¥; and ¤iii¥ CYP2D6*36 alone.41¥ Two polymorphic sites that are common in CYP2D6*2 are 2850ChT ¤R286C¥ and 4180GhC ¤S486T¥, but these also appear in other variants; for example CYP2D6*14, *21, *51, and *55 have both the polymorphic sites while CYP2D6 *10, *39, *47, *49, and *54 have a polymorphic variation of 4180GhC. CYP2D6*2 was thought to result in no enzymatic change compared to CYP2D6*1. However, Abduljalil et al.,82¥ reported a 2-fold higher activity of CYP2D6*1 compared to CYP2D6*2 in their study conducted to quantify the effects of the CYP2D6*1, *2, and *41 variants on dextromethorphan metabolism in 36 healthy Caucasian men. Geographical and Racial Differences of CYP2D6 Gene There are marked differences in CYP2D6 genotypes and phenotypes in populations of different racial origins.83,84¥ A systemic study of CYP sequence divergence across populations would be useful to help understand the evolution of CYPös enzymes. Certain alleles were found to occur at high frequency in different populations, for example, CYP2D6*4 in Caucasians, *10 in Asians and *17 in Africans. In Asia, CYP2D6*17 is either absent or occurs at low frequency. This shows that these mutations must have occurred after the separation of the respective populations from each other.84¥ There are pronounced differences in the prevalence of PMs and in the relative enzyme activity in different ethnic groups. The overall prevalence of PMs was 7 to 10% in Caucasian populations and was rare in other populations. In Asians, PMs occurred at 0®1%85®89¥ due to the low frequencies in Asia of CYP2D6*3 and *4, which were the most abundant null alleles in Caucasians,90¥ CYP2D6*2,*3,*4,*5,*6,*10 and *41 being more common in the Caucasian population, *2 and *17 more frequently observed in Africans and CYP2D6*10 and *36 more prevalent in Asians.91¥ It is interesting to note that the frequency of PMs remained relatively constant among Caucasians in different continents. Similarly, the Chinese, Thai, Singaporeans, Japanese, and Malaysian Malays85,87,92,93¥ also showed lower prevalence. However, despite their localization the New Zealand Maori had a frequency of PMs similar to that of Caucasians.94¥ CYP2D6*10 is the most common allele in Asians.25¥ The CYP2D6.10 enzyme has a P34S substitution resulting in an unstable enzyme with reduced affinity for CYP2D6 substrates.95¥ CYP2D6*10 has the hallmark nucleotide change of C to T at 100, which is also present in CYP2D6*4A, the most common inactivating allele in Caucasians. In Chinese, CYP2D6*10, comprises 51®70% of all the CYP2D6 alleles and results in a right shift in the median of metabolic ratio among Chinese extensive metabolisers ¤EMs¥.87,90,96¥ The mean enzyme activity of CYP2D6 was lower among Asians compared to Caucasians ¤Fig. 1¥. Another allele which was found commonly among Africans is CYP2D6*17.28¥ Among the Blacks, Masimirembwa et al.28¥ found a right shift of metabolic ratio metabolic ratio ¤MR¥ in Zimbabweans due to the presence of CYP2D6*17 and its frequency was 34% in Zimbabweans. The activity of the CYP2D6.17 enzyme is lower than that of the wild-type enzyme and the CYP2D6.17 enzyme showed an altered active site structure due to the two missense mutations seen in CYP2D6*2 and T107I. Different enzymatic effects have been shown with different substrates such as codeine, debrisoquine, dextromethorphan and metopolol.97¥ In contrast to the consistency of percentage of PMs, the percentage of duplicated/multiduplicated genes varies in different populations. In Swedish Caucasians, the frequency of subjects having duplicated/multiduplicated genes is about 1®2%.74¥ The frequency increases to 7®10% in Spain38,98¥ and becomes as high as 29% in black Ethiopians.74¥ Studies in Asian countries, revealed 1 to 2% of the Japanese, Chinese, Malays and Indians have gene duplication.71,93,99®101¥ In Figure 1, the distribution of the debrisoquine/4-hydroxydebrisoquine MR is bimodal in a large Swedish Caucasian population.102¥ PM have an MR higher than 12.6 and are homozygous for mutated alleles, to a major extent CYP2D6*4. UMs with low MR have multiple functional alleles. In one Swedish family, 13 active CYP2D6 genes have been demonstrated.13,103¥ Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) Pharmacogenomics of CYP2D6 Lower MR 57 Higher MR & “Right shift” Fig. 1. Distribution of the urinary debrisoquine MR in 757 healthy Swedish subjects with a schematic presentation of CYP2D6 genotypes, where a cross in an allele indicates a detrimental mutation Tentative doses of nortriptyline to be used in different genotypes are indicated.102) CYP2D6*36 is absent in white populations, but present in Asian and African American populations. CYP2D6*36 may have originated in Africa and spread to Asia but not Europe. CYP2D6*36 is accountable for the PM status in Asians and African Americans ¤3% and 0.5% respectively¥.41¥ Generally, the type and allele frequencies of CYP2D6 among Caucasians are different from those in Asians and Africans. Interestingly, Indians have similar types and frequencies of CYP2D6 alleles with Caucasians.100¥ They have lower frequencies of CYP2D6*10 and higher frequencies of *4 compared to the Japanese, Chinese and Malays. In fact, Indians are the eastern most settlement of the Caucasian úraceû and thus classified as Caucasians.104¥ Clinical Significance of Treatment with CYP2D6 Substrates The clinical significance of the genetic polymorphism of CYP2D6 will be reviewed with respect to its importance to pharmacokinetic variation and disease association. A number of factors govern the clinical importance of the polymorphism, which include the nature of the primary metabolism pathway and mechanism that activate the parent compound, the potency of the parent compound and its metabolite¤s¥, and the therapeutic windows of the drugs. A drug with an easily saturable metabolism tends to have a narrow therapeutic index, and the contribution of several pathways of elimination needs to be considered in the prediction of its effect. As one substrate may be metabolised by several different enzymes, the clinical impact of CYP2D6 dependent-metabolism needs to be carefully investigated for each substrate. This has been illustrated in a clinical context of accidental toxicity, whereby the precise dose of nortriptyline was determined by the combined effect of both CYP3A4 and CYP2D6.105¥ Another major impact of a genetic polymorphism for first-pass extraction can be expected for drugs with a high hepatic clearance. EMs may have low bioavailability of drugs with a high hepatic ¤and possibly intestinal¥ extraction while the extraction may be impaired in PMs and result in increased bioavailability. On the other hand, drugs with a low hepatic clearance can have a high bioavailability in EMs, which will be similar in PMs. However, the interphenotypic differences exist mainly if these drugs are administered orally. Genetic polymorphisms of CYP2D6 result in 4 phenotypes with significant clinical implication especially the PM and UM. PMs exhibit decreased metabolism of drugs and thus require lower dosages to avoid toxic effects. Adverse effects due to elevated drug plasma levels occur more frequently in PMs in cases where the drug clearance is dependent on CYP2D6.96¥ On the other hand, PMs can experience diminished effects with drugs that need to be metabolised to active compounds by CYP2D6. A popular example is codeine, which is a prodrug and needs to be converted to morphine in patients.106¥ Inadequate transformation in PMs leads to diminished pain relief or even tolerance/addiction. On the other extreme is the UMs who have more than two functional alleles due to gene duplication or multiplication. UMs would require lower doses of codeine than normal, since transformation of codeine to morphine is enhanced. UM patients given drugs active per se may be resistant to such treatment, and more time may be required to adjust the dosage before therapeutic efficacy is achieved. In theory, identifying a CYP2D6 UM Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) 58 Lay Kek TEH and Leif BERTILSSON Fig. 2. Graphical presentation of drug levels achieved in predicted phenotype of CYP2D6 from different alleles of CYP2D6 Parent drug: An active drug per se. Pro-drug: An inactive drug, converted into an active metabolite. up-front, would decrease the time needed to adjust a dosage upward, helping to achieve therapeutic success faster ¤Fig. 2¥. Recently, Black et al.,107¥ revisited the issue of CYP2D7-2D6 hybrid genes in samples with duplication signals and predicted UMs. Of 341 samples with duplication signals, 25 ¤7.3%¥ harbored an undetected CYP2D7-2D6 hybrid and had a change in predicted phenotype. Overestimation of UMs among clinical samples would result in higher doses recommended to patients and carries risks of toxicity. Genetic polymorphism of CYP2D6 and psychotropic drugs: Important findings have been described with respect to the role of CYP2D6 polymorphism for the clinical outcome of psychoactive drugs. Depending on the pharmacokinetic and pharmacodynamic properties of the administered drug, the impact of the functionality of the enzymes differs. The increased concentration of the parent drug or its active metabolites can result in an increased risk of toxicity or loss of therapeutic effect in PMs. On the other hand, UMs of CYP2D6 might require higher doses than recommended in order to achieve therapeutic drug levels. In one typical example, a patient was found to require high doses of nortriptyline ¤300®500 mg per day¥ to achieve õõtherapeuticöö plasma levels ¤200®600 nM¥.108¥ A debrisoquine phenotyping test confirmed that this patient was an UM of debrisoquine ¤and nortriptyline¥ with a metabolic ratio of 0.07. This metabolic ratio was one of the lowest seen in a Swedish population. In 1993, 8 years later, this patient was genotyped and found to have a duplication of the CYP2D6 gene and thus three functional genes, leading to an increased activity of the enzyme.109¥ Dalen et al.103¥ gave single oral doses of nortriptylline to healthy Swedish subjects with different numbers of active CYP2D6 alleles ¤Fig. 3¥. As expected the highest concen- tration of the parent drug was seen in subjects with zero active genes, i.e., PMs. The lowest concentration was seen in a subject with 13 genes ¤Fig. 3, left¥. The concentration of the 10-hydroxymetabolite were highest with 13 genes and lowest in PMs ¤Fig. 3, right¥. This demonstrates a clear gene-dose relationship.103¥ Between UMs and PMs, we have individuals classified as EMs. Morita et al.110¥ showed the influence of the CYP2D6*10 allele on the steady state plasma levels of nortriptyline and its 10-hydroxy metabolite in Japanese depressed patients. CYP2D6*10 encodes an enzyme with decreased activity to metabolise nortriptyline. This effect is less pronounced than that of the CYP2D6*4 allele, which encodes no enzyme at all. Genotyping or phenotyping for CYP2D6 may be a tool to predict proper initial dosing of drugs such as nortriptyline in individual patients, especially those with extremely low or high CYP2D6 activity. This can be demonstrated with our experience with two patients for whom the dosage of nortriptyline and other antidepressants needed to be individualized. The meta-analysis performed by Kirchheiner et al.111¥ reveals that the dosage of about 50% of antidepressants used is very dependent on the CYP2D6 genotype and is most important. In a study of 100 consecutive psychiatric inpatients genotyped for CYP2D6 on admission, the number of adverse effects in patients treated with CYP2D6 substrates was highest in PMs and higher in intermediate metabolisers ¤IMs¥ than in EMs or UMs.112¥ With respect to the treatment of schizophrenia with perphenazine, thioridazine or haloperidol, significant oversedation has been found to be linked to the CYP2D6 genotype in three different studies. Increased frequency of Parkinsonism was seen in two studies as reviewed by Dahl,113¥ whereas no significant relationship has been seen Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) Pharmacogenomics of CYP2D6 59 Fig. 3. Mean plasma concentrations of nortriptyline (left) and 10-hydroxynortriptyline (right) in different CYP2D6 genotype groups after a single oral dose of nortriptyline The numerals close to the curves represent the number of functional CYP2D6 genes in each genotype group. In groups with 0–3 functional genes, there were five subjects in each group while there was only one subject with 13 functional genes. Reproduced with permission from Dalén et al.103) to tardive dyskinesia, acute dystonia, or akathisia. The relationship to parkinsonism has also been documented in several other studies. For example, in an investigation where 77 patients prescribed CYP2D6-dependent antipsychotic drugs and 55 patients prescribed non-CYP2D6 dependent antipsychotic drugs were studied, it was revealed that PMs were four times more likely to start with antiparkinsonian medication.114¥ Drugs against parkinsonian side effects were given twice more frequently in PMs among 241 psychiatric patients.115¥ In a thorough study it was found that haloperidol clearance correlated with the number of active CYP2D6 genes. Ratings for pseudoparkinsonism were higher in PMs and a trend towards lower therapeutic efficacy with increasing number of active CYP2D6 genes was seen. In addition, genotyping was as good predictor of adverse drug reactions ¤ADRs¥ as measurements of drug concentrations.116¥ Side effects among PMs have often been registered. In addition, nonresponsiveness to antidepressant therapy is a serious problem and has been found to be associated with the multi/duplicated copies of CYP2D6 in a pilot study.117¥ Subjects who were UMs were highly over-represented in the non-responder group as compared to the control population. The association of UMs and nonresponders to antidepressants requires further prospective studies especially in the Mediterranean area where the frequency of CYP2D6 gene duplications is much higher than in Northern Europe.98¥ Genotyping for CYP2D6 in psychiatric patients might be useful to diagnose PM and UM patients treated with antidepressant or neuroleptic drugs. A combination of genotype and phenotype i.e., determination of plasma drug concentration would be recommended. A low plasma concentration of nortriptylline or haloperidol could be due to CYP2D6 gene duplication or poor compliance. This may be shown by the presence or absence of multiple CYP2D6 genes. CYP2D6 and treatment of cardiovascular disorders: Studying CYP2D6 polymorphism in cardiovascular patients has relevance because this enzyme metabolises 30 to 50 drugs,118¥ many of which are cardiovascular drugs. In PMs such drugs would often be handled as a low intrinsic clearance drug with the oral bioavailability markedly increased and the half-life prolonged. This would be reflected by increases in the peak plasma concentrations after oral dosing and increases in the steady state plasma concentrations during chronic dosing. Several drug substrates of the polymorphic enzyme are also sometimes used concurrently in patients with cardiovascular diseases, and the treatment results in many such situations may not be or would be difficult to be monitored by objective parameters. Goryachkina et al.119¥ investigated patients with an acute myocardial infarction treated with metoprolol, a typical CYP2D6 substrate. When such patients developed a depression, they were co-treated with paroxetine, a potent inhibitor of CYP2D6. Paroxetine inhibited the metabolism of metoprolol and potentiated its effects by increasing the maximum concentration of both S- and R-metoprolol.120¥ Furthermore, patients with cardiovascular diseases are generally older than 50 years and many are more than 65 years. In older patients, complications from pharmacotherapy constitute a highly significant health problem. Adverse reactions to drugs of all types are seven times higher in those aged 70 to 79 years than in those who are 20 to 29 years old121¥ and concomitant administration of interacting drugs would be expected to add to the problems. Cases of drug-drug interaction were reviewed in a group of 100 elderly patients with an average of more than 5 prescribed drugs. Eighty percent of the patients had at least 1 incidence of drug-drug interaction and 22.7% of the cases were due to concurrent use of CYP2D6 substrates or inhibitors.122¥ Drugs used in cardiovascular patients are also usually for a long-term therapy and adverse reactions may be increased especially when patients also go on their own to use over the counter drugs ¤OTC¥123¥ and probably herbal medicines which may be CYP2D6 substrates or inhibitors. For example, berberine, which is a plant alkaloid widely Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) 60 Lay Kek TEH and Leif BERTILSSON used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia, has been found to decrease CYP2D6, 2C9, and CYP3A4 activities.124¥ Further suggestions on the importance of the genetic polymorphism of drug metabolizing enzymes on cardiovascular diseases can be seen from studies such as that of Thum and Borlakös.125¥ These authors investigated the gene expression of major human cytochrome P450 genes in the heart. They found that mRNA for CYP2D6 was predominantly expressed in the right ventricle. A strong correlation between tissue-specific gene expression and enzyme activity was also found. Monohydroxylation of the antianginal agent perhexiline is almost exclusively catalysed by CYP2D6 with activities being about 100-fold lower in CYP2D6 PMs than in EMs.126¥ Perhexiline has a concentration-related hepatotoxicity and peripheral neuropathy and determination of the CYP2D6 genotype will predict dose requirements and reduce the risk of perhexiline concentration-related toxicity.127¥ In a retrospective study, Wuttke et al.128¥ identified 24 patients treated with metoprolol who had experienced pronounced adverse effects. Genotyping revealed a five-fold higher frequency of PMs in this group ¤38%¥ as compared to the control population. As many of the drugs used to treat cardiovascular diseases have a wide therapeutic window, the impact of CYP2D6 polymorphism becomes less significant. As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics with 30-fold variability in area under the curve ¤AUC¥ among EMs. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and Çblocker-induced adverse effects or efficacy.129¥ Genetic polymorphism of CYP2D6 and tamoxifen: Genetic polymorphisms of CYP2D6 have been reported as the major cause of variation in the metabolism of tamoxifen that leads to adverse effects or lack of therapeutic efficacy. The US Food and Drug Administration ¤FDA¥ advisory committee has recommended labeling changes to indicate that post-menopausal estrogen receptor ¤ER¥ positive breast cancer patients who are taking adjuvant tamoxifen and are homozygous CYP2D6*4/*4 have significantly decreased relapse-free survival compared to those with the heterozygous or homozygous wild type of CYP2D6.130,131¥ However the FDA has not recommended routine testing of all women on tamoxifen for risk stratification. In addition, there were no comments on the impact of several variants such as CYP2D6 *5,*10, and*41 and ethnic variation. Wide interpatient variations in responses to tamoxifen have been observed across populations where administration of the same dose of this drug results in a range of outcomes which include adverse events or therapeutic failure. Among Caucasians, tamoxifen-treated patients carrying the heterozygous and homozygous CYP2D6*4 had a significantly increased risk of recurrence of breast cancer, shorter relapse-free periods and worse event-free survival rates compared with carriers of functional alleles.130,131¥ A recent study among breast cancer patients with CYP2D6*10/*10 in Asians has shown that the steady state plasma levels of 4-hydroxytamoxifen and endoxifen were significantly lower. In addition, breast cancer patients with CYP2D6*10/*10 had significantly shorter median time to disease progression compared to patients who were homozygous wild-type or heterozygotes.132®134¥ Furthermore, breast cancer patients who received adjuvant tamoxifen therapy revealed worse therapy outcomes in patients with the CYP2D6*10/*10 genotype and significantly higher incidence of recurrence within 10 years after the operation.133,135¥ In a Japanese study, women who had the CYP2D6*10/*10 genotype had a significantly higher incidence of recurrence within 10 years compared to women with the wild type genotype ¤CYP2D6*1/*1¥. Patients with genotype CYP2D6*10/*10 showed shorter recurrence-free survival relative to the wild type ¤CYP2D6*1/*1¥. The results of a Chinese study of 152 women with breast cancer receiving tamoxifen were also supportive.135¥ The study observed that the serum levels of 4-hydroxy-tamoxifen were reduced in patients bearing the homozygous CYP2D6*10/*10 genotype relative to the wild type. They also observed that disease-free survival was reduced in tamoxifen-treated women who had CYP2D6*10/ *10 genotype expression relative to wild type. In a Dutch population, the risk of death due to breast cancer was significantly increased in tamoxifen users with the CYP2D6*4/*4 genotype. The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users.137¥ In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, and prior knowledge of CYP2D6 testing, the patientsö CYP2D6 genotype was found to be the only significant factor that predicted a change in the choice of hormonal therapy.137¥ Kiyotani et al.138¥ evaluated the usefulness of knowledge of CYP2D6 genotypes in 98 Japanese breast cancer patients who had been taking 20 mg of tamoxifen daily as an adjuvant setting. For the patients who had one or no normal allele of CYP2D6, dosages of tamoxifen were increased to 30 and 40 mg/day, respectively. Dose adjustment was found to be appropriate in the patients carrying the CYP2D6*10 allele to maintain an effective endoxifen level. These findings are important to predict the effectiveness and resistance of tamoxifen therapy among breast cancer patients. These lines of evidence also imply that pregenotyping of CYP2D6 intermediate metaboliser is important before prescribing tamoxifen. These results confirmed the findings of previous studies and support FDA recommendation to perform pre-genotyping in patients before the choice of therapy is determined in breast cancer patients. In contrast, two studies from Japan showed that the CYP2D6*10/*10 genotype was unlikely to have any clinical significance on breast cancer patients receiving adjuvant tamoxifen.139,140¥ Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) 61 Pharmacogenomics of CYP2D6 CYP2D6 And Drug Interactions and Clinical Implication As CYP2D6 plays an important role in the metabolism of at least 25% of the marketed drugs, there are possible issues of drug interactions in vivo which are of clinical significance. Substrates with a high affinity bind strongly to CYP2D6 and would result in inhibition of the metabolism of other compounds which have lower affinity. Consequently, drug interactions occur in EMs, but not in PMs as they do not have CYP2D6 enzymes to compete for. Another issue that requires attention is phenocopying, whereby an EM would be phenotypically poor if he was concurrently prescribed a strong inhibitor of CYP2D6. The first pass metabolism of the substrate might be inhibited and the rate of elimination prolonged resulting in higher plasma concentration and toxicity. On the other hand, inhibition of metabolism by CYP2D6 causes lack of therapeutic response when the pharmacological action is dependent on the transformation of pro-drugs to active metabolites. Since CYP2D6 is not inducible, drug interactions due to enzyme induction are very unlikely to occur. Several drugs have been used concurrently in clinical situations and impair the metabolism catalysed by CYP2D6. Potent inhibition of CYP2D6 has been observed when selective serotonin reuptake inhibitors ¤SSRIs¥ are used to reduce hot flushes in women with breast cancer, but results in decreased plasma concentrations of the active metabolite endoxifen. Thus the use of the SSRIs that are potent CYP2D6 inhibitors ¤e.g., paroxetine and fluoxetine¥ concurrently with tamoxifen may be associated with poorer outcomes and should be avoided as far as possible.141¥ The NCCTG 89-30-52 trial analysed the co-prescription of CYP2D6 inhibitors and CYP2D6 metaboliser status and concluded that the clinical benefit of tamoxifen was significantly decreased in patients with decreased CYP2D6 activity either due to the PM genotype or the concurrent use of CYP2D6 inhibitors.142¥ In addition to drug-drug interaction, cautious use of herbal medicine should be practiced to avoid drug-herb interactions. For example, the alkaloids protopine and allocryptopine in black cohosh were identified as competitive CYP2D6 inhibitors and thus should be used with caution in breast cancer patients treated with tamoxifen.143¥ Similarly, concurrent use of Hypericum extract should be avoided in patients treated with SSRIs.144¥ In 2000 Hamelin et al. reported interaction of nonpresription drugs with CYP2D6 substrates.123¥ There was a 61% increment in the AUC of metoprolol when diphenhydramine was co-administered in EMs. A significant aggravation of metoprolol-related effects such as decrease in heart rate, systolic blood pressure, and Doppler-assessed aortic blood flow was observed after administration of diphenhydramine. Even though metoprolol has a wide therapeutic window, the interaction can be severe especially because many older patients with multiple co-morbidities take both of these drugs simultaneously. CYP2D6 and Disease Susceptibility The CYP2D6 phenotype and genotype has been investigated with respect to the risk of cancers and other diseases. Individuals who were EMs because of CYP2D6 had higher risks of malignant processes as increased metabolism of one or more agents in the diet or other environmental agents, mediated by CYP2D6, forms reactive intermediaries that influence the initiation or promotion of cancer in various tissues.145¥ It has been found that polymorphism at loci that encode carcinogen-metabolizing enzymes such as cytochrome P450, which catalyzes the detoxification of carcinogens, may determine susceptibility to cancer. On the other hand, PMs must be exposed longer to the toxic effects of non-metabolised drugs and numerous other factors to have increased risks of cancers. The types of cancer that were evaluated included melanoma, lung-, breast-, anogenital-, basal cell- aerodigestive tract-, oral-, prostate-, pancreatic- and bladder-cancer. Association was observed between the CYP2D6 gene and lung cancer,146¥ bladder cancer147¥ and oral cancer.148¥ London et al.149¥ found that the CYP2D6 genetic polymorphism is not a strong risk factor for lung cancer. Smith et al.150¥ and Goetz et al.151¥ stated that CYP2D6 genotype is not the causal factor for breast cancer. Meanwhile, reduced CYP2D6 activity ¤PM¥ has been related to greater risk of leukemia and oral cancer.148¥ There is however a lack of consistency in the results observed, and a clear distinction between the EM and PM phenotypes with regard to susceptibility to cancer cannot be established. CYP2D6s are found in the brain and they are similar to those found in the liver and thus studies have attempted to associate their role with CNS disorder. Researchers hypothesized that CYP2D6 may play an essential role in the biological activity as it is expressed in the brain. In fact, two studies have indicated a significant relationship between CYP2D6 and behavior, using psychological tests and the presence of CYP2D6.152,153¥ It was shown that there was a higher number carrying more than two active CYP2D6 genes ¤gene duplication¥ among those who died of suicide ¤suicide cases¥, as compared with those who died of natural causes ¤natural-death cases¥ ¤p © 0.007¥.154¥ It was suggested that CYP2D6 transforms 5-methoxy tryptamine to serotonin in the brain of suicide attempters.155¥ Several studies have indicated serotonergic hypofunction in suicidal behavior.156¥ These studies suggest that CYP2D6 in the human brain is important for behavior. Interestingly, Pai et al.157¥ have provided evidence that a common variant of the pseudogene CYP2D7 could be expressed in an active form in human brain yielding a functional enzyme that is active in the metabolism of codeine. Allelic variation at the CYP2D6 gene has been suggested to be associated with CNS disorders, includ- Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) 62 Lay Kek TEH and Leif BERTILSSON ing Parkinsonös disease ¤PD¥, Lewy body dementia and Alzheimerös.158¥ Poor CYP2D6 metabolisers were are at higher risk for PD due to their reduced ability to inactivate PD-causing neurotoxins. Patients with PD cases had approximately 40% lower CYP2D6 levels in the frontal cortex, cerebellum, and hippocampus.159¥ However, the CYP2D6 genotypes related disease risk are conflicting due to the small sample size and the heterogenous nature of the diseases, the sampling and nature of agematching, and the polygenic nature of these diseases.160¥ In addition, the genotypes screened in each study may be limited and not comprehensive enough to provide conclusive data. Conclusion CYP2D6 is highly polymorphic and heterogenous. The type and frequencies of alleles show ethnic specificities. The clinical impact of genetic polymorphism of drug metabolism enzymes is higher in drugs with a narrow therapeutic window and only one metabolic pathway is involved with more than 90% of the metabolism. Many of the drugs today are designed to share more than one drug metabolizing enzyme. This would increase the market population as severe toxicity due to impaired functionality of one enzyme would be reduced. However, toxicity due to drug interaction may occur due to phenocopying and special attention is required. Thus far, pre-genotyping of CYP2D6 before drugs are prescribed is recommended for tamoxifen, antidepressants and antipsychotics to identify those special patients who may need to have the dosage adjusted. In Caucasians, the risk of adverse effects due to poor metabolism would be higher than in Asians. Asians have a lower capability to metabolise CYP2D6 substrates but as most of the CYP2D6 substrates do not have narrow therapeutic windows, the clinical impact is less obvious. 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