Pharmacogenomics of CYP2D6: Molecular Genetics ... Pharmacogenomics of CYP2D6: Molecular Genetics, Interethnic Differences and Clinical Importance Lay Kek TEH1,* and Leif BERTILSSON2

Review

Pharmacogenomics of CYP2D6: Molecular Genetics,Interethnic Differences and Clinical Importance

Lay Kek TEH1,* and Leif BERTILSSON 2

1Pharmacogenomics Centre (PROMISE), Faculty of Pharmacy, Universiti Teknologi MARA, Malaysia2Division 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 the1970s. This is because of its involvement in the metabolism of more than 25% of the marketed drugs, thelarge geographical and inter-ethnic differences in the genetic polymorphism and possible drug-inducedtoxicity. Many interesting reviews have been published on CYP2D6 and this review aims to reinstate theimportance of the genetic polymorphism of CYP2D6 in different populations as well as some clinicalimplications and important drug interactions.

Keywords: CYP2D6 polymorphism; interethnic differences; clinical implication

CYP2D6 Genetic Polymorphism

Cytochrome P450 ¤CYP¥ 2D6 is one of the mostwidely investigated CYPs in relation to genetic poly-morphism. Typical substrates for CYP2D6 are largelylipophilic in nature and include antidepressants, antipsy-chotics, antiarrhythmics, antiemetics, beta-adrenoceptorantagonists ¤beta-blockers¥ and opioids, which representapproximately 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 forthe large research interest of this enzyme is the wideinter-individual variation in the enzyme activity of CYP2Dwhich led to discovery of deletion and duplication ofthe CYP2D6 gene. In addition, the discovery of CYP2D6polymorphism7®9¥ has created new interest in the roleof pharmacogenetics in clinical pharmacology since the1970s.

Molecular Genetics of CYP2D6

CYP2D6 is the only functional gene in the CYP2Dsubfamily of the human genome.10¥ To date, more than 80allelic variants have been reported for CYP2D6 ¤http://www.imm.ki.se/cypalleles/cyp2d6.htm¥. The most com-mon functional polymorphism in drug metabolizing en-zymes ¤DMEs¥ is point mutations in coding regions of the

CYP2D6 gene resulting in amino acid substitutions, whichalter catalytic activity, enzyme stability, and/or substratespecificity.The CYP2D6 gene is localized on chromosome 22q13.1. It

contains 9 exons11¥ within 4,383 bp based on the NCBI 37genome assembly. The evolution of the human CYP2D locushas involved elimination of three genes and inactivation oftwo neighbouring genes ¤CYP2D7 and CYP2D8P¥ and partialinactivation of one CYP2D6. These genes display 92®97%nucleotide similarity across their introns and exons. TheCYP2D8P gene was found to be a pseudogene and to containseveral gene-disrupting insertions, deletions, and termina-tion codons within its exons. CYP2D7, which is justdownstream of CYP2D8P, is apparently normal, except forthe presence, in the first exon, of an insertion that disruptsthe reading frame. These two closely related genes werebelieved to transfer detrimental mutations via geneconversions into the CYP2D6 gene and were hypothesisedto account for the high prevalence of variants which mostcommonly 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 CYP2D6enzyme activity. These alleles include 7 normal or increasedactivity 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¥

Received October 9, 2011; Accepted December 6, 2011J-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, UniversitiTeknologi MARA, 42300 Puncak Alam, Selangor DE, Malaysia. Tel. +603-32584685, Fax. +603-32584602, E-mail: [email protected]/[email protected]

Drug Metab. Pharmacokinet. 27 (1): 5567 (2012). Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

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http://www.jstage.jst.go.jp/browse/dmpk

http://www.imm.ki.se/cypalleles/cyp2d6.htm

http://www.imm.ki.se/cypalleles/cyp2d6.htm

http://dx.doi.org/10.2133/dmpk.DMPK-11-RV-121

*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 nonfunctionalalleles 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¥

*36,15,25,41,60¥ *38,60¥*40,61¥ *42,62¥ *44,58¥ *47 & *51,15,20¥

*56,63,64¥ *6265¥«, and many functionally undetermined allelesª*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 thenormal, nonfunctional, and reduced activity CYP2D6 allelesare observed, and these have been associated with variationof in vivo CYP2D6 enzyme activity. For example, morethan 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 toelevate CYP2D6 enzyme activity. Individuals who inheritthese 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 whoinherit these alleles do not have increased metabolism ofCYP2D6 substrates. In contrast to gaining extra copies ofthe CYP2D6 gene, CYP2D6*5 is a loss of gene copy thatproduces no CYP2D6 protein.42¥ Individuals with twononfunctional CYP2D6 alleles, including CYP2D6*5, have noCYP2D6 activity, and are classified as poor metabolisers¤PMs¥. It is noteworthy that CYP2D6*36, which has negli-gible 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 atandem arrangement with *10¥; and ¤iii¥ CYP2D6*36 alone.41¥

Two polymorphic sites that are common in CYP2D6*2are 2850ChT ¤R286C¥ and 4180GhC ¤S486T¥, but thesealso 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 variationof 4180GhC. CYP2D6*2 was thought to result in no enzy-matic change compared to CYP2D6*1. However, Abduljalilet al.,82¥ reported a 2-fold higher activity of CYP2D6*1compared to CYP2D6*2 in their study conducted to quantifythe effects of the CYP2D6*1, *2, and *41 variants ondextromethorphan metabolism in 36 healthy Caucasian men.

Geographical and Racial Differencesof CYP2D6 Gene

There are marked differences in CYP2D6 genotypes andphenotypes in populations of different racial origins.83,84¥ Asystemic study of CYP sequence divergence across popula-tions would be useful to help understand the evolution ofCYPös enzymes. Certain alleles were found to occur at highfrequency in different populations, for example, CYP2D6*4in Caucasians, *10 in Asians and *17 in Africans. In Asia,CYP2D6*17 is either absent or occurs at low frequency. Thisshows that these mutations must have occurred after theseparation of the respective populations from each other.84¥

There are pronounced differences in the prevalence ofPMs and in the relative enzyme activity in different ethnicgroups. The overall prevalence of PMs was 7 to 10% inCaucasian populations and was rare in other populations.In Asians, PMs occurred at 0®1%85®89¥ due to thelow frequencies in Asia of CYP2D6*3 and *4, whichwere the most abundant null alleles in Caucasians,90¥

CYP2D6*2,*3,*4,*5,*6,*10 and *41 being more commonin the Caucasian population, *2 and *17 more frequentlyobserved in Africans and CYP2D6*10 and *36 moreprevalent in Asians.91¥ It is interesting to note that thefrequency of PMs remained relatively constant amongCaucasians in different continents. Similarly, the Chinese,Thai, Singaporeans, Japanese, and Malaysian Malays85,87,92,93¥

also showed lower prevalence. However, despite theirlocalization the New Zealand Maori had a frequency ofPMs similar to that of Caucasians.94¥

CYP2D6*10 is the most common allele in Asians.25¥ TheCYP2D6.10 enzyme has a P34S substitution resulting in anunstable enzyme with reduced affinity for CYP2D6 sub-strates.95¥ CYP2D6*10 has the hallmark nucleotide changeof C to T at 100, which is also present in CYP2D6*4A, themost common inactivating allele in Caucasians. In Chinese,CYP2D6*10, comprises 51®70% of all the CYP2D6 allelesand results in a right shift in the median of metabolicratio among Chinese extensive metabolisers ¤EMs¥.87,90,96¥

The mean enzyme activity of CYP2D6 was lower amongAsians compared to Caucasians ¤Fig. 1¥.Another allele which was found commonly among Afri-

cans is CYP2D6*17.28¥ Among the Blacks, Masimirembwaet al.28¥ found a right shift of metabolic ratio metabolic ratio¤MR¥ in Zimbabweans due to the presence of CYP2D6*17and its frequency was 34% in Zimbabweans. The activity ofthe CYP2D6.17 enzyme is lower than that of thewild-type enzyme and the CYP2D6.17 enzyme showed analtered active site structure due to the two missensemutations seen in CYP2D6*2 and T107I. Different enzy-matic effects have been shown with different substratessuch as codeine, debrisoquine, dextromethorphan andmetopolol.97¥

In contrast to the consistency of percentage of PMs, thepercentage of duplicated/multiduplicated genes varies indifferent populations. In Swedish Caucasians, the frequencyof subjects having duplicated/multiduplicated genes is about1®2%.74¥ The frequency increases to 7®10% in Spain38,98¥

and becomes as high as 29% in black Ethiopians.74¥ Studies inAsian countries, revealed 1 to 2% of the Japanese, Chinese,Malays and Indians have gene duplication.71,93,99®101¥ InFigure 1, the distribution of the debrisoquine/4-hydrox-ydebrisoquine MR is bimodal in a large Swedish Caucasianpopulation.102¥ PM have an MR higher than 12.6 and arehomozygous for mutated alleles, to a major extentCYP2D6*4. UMs with low MR have multiple functionalalleles. In one Swedish family, 13 active CYP2D6 genes havebeen demonstrated.13,103¥

Lay Kek TEH and Leif BERTILSSON56

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

CYP2D6*36 is absent in white populations, but present inAsian and African American populations. CYP2D6*36 mayhave originated in Africa and spread to Asia but not Europe.CYP2D6*36 is accountable for the PM status in Asians andAfrican Americans ¤3% and 0.5% respectively¥.41¥

Generally, the type and allele frequencies of CYP2D6among Caucasians are different from those in Asians andAfricans. Interestingly, Indians have similar types andfrequencies of CYP2D6 alleles with Caucasians.100¥ Theyhave lower frequencies of CYP2D6*10 and higher frequenciesof *4 compared to the Japanese, Chinese and Malays. In fact,Indians are the eastern most settlement of the Caucasianúraceû and thus classified as Caucasians.104¥

Clinical Significance of Treatmentwith CYP2D6 Substrates

The clinical significance of the genetic polymorphism ofCYP2D6 will be reviewed with respect to its importance topharmacokinetic variation and disease association. A numberof factors govern the clinical importance of the poly-morphism, which include the nature of the primarymetabolism pathway and mechanism that activate the parentcompound, the potency of the parent compound and itsmetabolite¤s¥, and the therapeutic windows of the drugs. Adrug with an easily saturable metabolism tends to have anarrow therapeutic index, and the contribution of severalpathways of elimination needs to be considered in theprediction of its effect. As one substrate may be metabolisedby several different enzymes, the clinical impact of CYP2D6dependent-metabolism needs to be carefully investigatedfor each substrate. This has been illustrated in a clinicalcontext of accidental toxicity, whereby the precise dose of

nortriptyline was determined by the combined effect ofboth CYP3A4 and CYP2D6.105¥

Another major impact of a genetic polymorphism forfirst-pass extraction can be expected for drugs with a highhepatic clearance. EMs may have low bioavailability ofdrugs with a high hepatic ¤and possibly intestinal¥ extractionwhile the extraction may be impaired in PMs and resultin increased bioavailability. On the other hand, drugswith a low hepatic clearance can have a high bioavailabilityin EMs, which will be similar in PMs. However, theinterphenotypic differences exist mainly if these drugs areadministered orally.Genetic polymorphisms of CYP2D6 result in 4 phenotypes

with significant clinical implication especially the PMand UM. PMs exhibit decreased metabolism of drugs andthus require lower dosages to avoid toxic effects. Adverseeffects due to elevated drug plasma levels occur morefrequently in PMs in cases where the drug clearance isdependent on CYP2D6.96¥ On the other hand, PMs canexperience diminished effects with drugs that need to bemetabolised to active compounds by CYP2D6. A popularexample is codeine, which is a prodrug and needs to beconverted to morphine in patients.106¥ Inadequate trans-formation in PMs leads to diminished pain relief or eventolerance/addiction. On the other extreme is the UMswho have more than two functional alleles due to geneduplication or multiplication. UMs would require lowerdoses of codeine than normal, since transformation ofcodeine to morphine is enhanced. UM patients given drugsactive per se may be resistant to such treatment, and moretime may be required to adjust the dosage before therapeuticefficacy is achieved. In theory, identifying a CYP2D6 UM

Higher MR & “Right shift” Lower MR

Fig. 1. Distribution of the urinary debrisoquine MR in 757 healthy Swedish subjects with a schematic presentation of CYP2D6genotypes, where a cross in an allele indicates a detrimental mutationTentative doses of nortriptyline to be used in different genotypes are indicated.102)

Pharmacogenomics of CYP2D6 57


up-front, would decrease the time needed to adjust a dosageupward, helping to achieve therapeutic success faster¤Fig. 2¥. Recently, Black et al.,107¥ revisited the issue ofCYP2D7-2D6 hybrid genes in samples with duplicationsignals and predicted UMs. Of 341 samples with duplicationsignals, 25 ¤7.3%¥ harbored an undetected CYP2D7-2D6hybrid and had a change in predicted phenotype. Over-estimation of UMs among clinical samples would result inhigher doses recommended to patients and carries risks oftoxicity.Genetic polymorphism of CYP2D6 and psycho-

tropic drugs: Important findings have been describedwith respect to the role of CYP2D6 polymorphism for theclinical outcome of psychoactive drugs. Depending on thepharmacokinetic and pharmacodynamic properties of theadministered drug, the impact of the functionality of theenzymes differs. The increased concentration of the parentdrug or its active metabolites can result in an increasedrisk of toxicity or loss of therapeutic effect in PMs. Onthe other hand, UMs of CYP2D6 might require higherdoses than recommended in order to achieve therapeuticdrug levels. In one typical example, a patient was found torequire high doses of nortriptyline ¤300®500mg per day¥ toachieve õõtherapeuticöö plasma levels ¤200®600 nM¥.108¥ Adebrisoquine phenotyping test confirmed that this patientwas an UM of debrisoquine ¤and nortriptyline¥ with ametabolic ratio of 0.07. This metabolic ratio was one of thelowest seen in a Swedish population. In 1993, 8 years later,this patient was genotyped and found to have a duplicationof the CYP2D6 gene and thus three functional genes, leadingto an increased activity of the enzyme.109¥

Dalen et al.103¥ gave single oral doses of nortriptylline tohealthy Swedish subjects with different numbers of activeCYP2D6 alleles ¤Fig. 3¥. As expected the highest concen-

tration of the parent drug was seen in subjects with zeroactive genes, i.e., PMs. The lowest concentration was seenin a subject with 13 genes ¤Fig. 3, left¥. The concentrationof the 10-hydroxymetabolite were highest with 13 genes andlowest in PMs ¤Fig. 3, right¥. This demonstrates a cleargene-dose relationship.103¥

Between UMs and PMs, we have individuals classifiedas EMs. Morita et al.110¥ showed the influence of theCYP2D6*10 allele on the steady state plasma levels ofnortriptyline and its 10-hydroxy metabolite in Japanesedepressed patients. CYP2D6*10 encodes an enzyme withdecreased activity to metabolise nortriptyline. This effect isless pronounced than that of the CYP2D6*4 allele, whichencodes no enzyme at all. Genotyping or phenotyping forCYP2D6 may be a tool to predict proper initial dosing ofdrugs such as nortriptyline in individual patients, especiallythose with extremely low or high CYP2D6 activity. This canbe demonstrated with our experience with two patients forwhom the dosage of nortriptyline and other antidepressantsneeded to be individualized.The meta-analysis performed by Kirchheiner et al.111¥

reveals that the dosage of about 50% of antidepressantsused is very dependent on the CYP2D6 genotype and ismost important. In a study of 100 consecutive psychiatricinpatients genotyped for CYP2D6 on admission, the numberof adverse effects in patients treated with CYP2D6substrates was highest in PMs and higher in intermediatemetabolisers ¤IMs¥ than in EMs or UMs.112¥

With respect to the treatment of schizophrenia withperphenazine, thioridazine or haloperidol, significant over-sedation has been found to be linked to the CYP2D6 geno-type in three different studies. Increased frequency ofParkinsonism was seen in two studies as reviewed byDahl,113¥ whereas no significant relationship has been seen

Fig. 2. Graphical presentation of drug levels achieved in predicted phenotype of CYP2D6 from different alleles of CYP2D6Parent drug: An active drug per se. Pro-drug: An inactive drug, converted into an active metabolite.



to tardive dyskinesia, acute dystonia, or akathisia. Therelationship to parkinsonism has also been documented inseveral other studies. For example, in an investigation where77 patients prescribed CYP2D6-dependent antipsychoticdrugs and 55 patients prescribed non-CYP2D6 dependentantipsychotic drugs were studied, it was revealed that PMswere four times more likely to start with antiparkinsonianmedication.114¥ Drugs against parkinsonian side effects weregiven twice more frequently in PMs among 241 psychiatricpatients.115¥

In a thorough study it was found that haloperidolclearance correlated with the number of active CYP2D6genes. Ratings for pseudoparkinsonism were higher in PMsand a trend towards lower therapeutic efficacy withincreasing number of active CYP2D6 genes was seen. Inaddition, genotyping was as good predictor of adverse drugreactions ¤ADRs¥ as measurements of drug concentrations.116¥

Side effects among PMs have often been registered. Inaddition, nonresponsiveness to antidepressant therapy is aserious problem and has been found to be associated with themulti/duplicated copies of CYP2D6 in a pilot study.117¥

Subjects who were UMs were highly over-represented inthe non-responder group as compared to the controlpopulation. The association of UMs and nonresponders toantidepressants requires further prospective studies especiallyin the Mediterranean area where the frequency of CYP2D6gene duplications is much higher than in Northern Europe.98¥

Genotyping for CYP2D6 in psychiatric patients might beuseful to diagnose PM and UM patients treated withantidepressant or neuroleptic drugs. A combination ofgenotype and phenotype i.e., determination of plasma drugconcentration would be recommended. A low plasmaconcentration of nortriptylline or haloperidol could be dueto CYP2D6 gene duplication or poor compliance. This may beshown by the presence or absence of multiple CYP2D6 genes.CYP2D6 and treatment of cardiovascular disor-

ders: Studying CYP2D6 polymorphism in cardiovascularpatients has relevance because this enzyme metabolises 30 to

50 drugs,118¥ many of which are cardiovascular drugs. InPMs such drugs would often be handled as a low intrinsicclearance drug with the oral bioavailability markedlyincreased and the half-life prolonged. This would bereflected by increases in the peak plasma concentrationsafter oral dosing and increases in the steady state plasmaconcentrations during chronic dosing.Several drug substrates of the polymorphic enzyme are

also sometimes used concurrently in patients with cardio-vascular diseases, and the treatment results in many suchsituations may not be or would be difficult to be monitoredby objective parameters. Goryachkina et al.119¥ investigatedpatients with an acute myocardial infarction treated withmetoprolol, a typical CYP2D6 substrate. When suchpatients developed a depression, they were co-treated withparoxetine, a potent inhibitor of CYP2D6. Paroxetineinhibited the metabolism of metoprolol and potentiated itseffects by increasing the maximum concentration of bothS- and R-metoprolol.120¥

Furthermore, patients with cardiovascular diseases aregenerally older than 50 years and many are more than 65years. In older patients, complications from pharmaco-therapy constitute a highly significant health problem.Adverse reactions to drugs of all types are seven timeshigher in those aged 70 to 79 years than in those who are20 to 29 years old121¥ and concomitant administration ofinteracting drugs would be expected to add to the problems.Cases of drug-drug interaction were reviewed in a groupof 100 elderly patients with an average of more than 5prescribed drugs. Eighty percent of the patients had at least1 incidence of drug-drug interaction and 22.7% of the caseswere due to concurrent use of CYP2D6 substrates orinhibitors.122¥ Drugs used in cardiovascular patients are alsousually for a long-term therapy and adverse reactions may beincreased especially when patients also go on their own touse over the counter drugs ¤OTC¥123¥ and probably herbalmedicines which may be CYP2D6 substrates or inhibitors.For example, berberine, which is a plant alkaloid widely

Fig. 3. Mean plasma concentrations of nortriptyline (left) and 10-hydroxynortriptyline (right) in different CYP2D6 genotype groupsafter a single oral dose of nortriptylineThe numerals close to the curves represent the number of functional CYP2D6 genes in each genotype group. In groups with 0–3 functionalgenes, there were five subjects in each group while there was only one subject with 13 functional genes. Reproduced with permission fromDalén et al.103)



used to treat gastrointestinal infections, diabetes, hyper-tension, and hypercholesterolemia, has been found todecrease CYP2D6, 2C9, and CYP3A4 activities.124¥

Further suggestions on the importance of the geneticpolymorphism of drug metabolizing enzymes on cardio-vascular diseases can be seen from studies such as that ofThum and Borlakös.125¥ These authors investigated thegene expression of major human cytochrome P450 genesin the heart. They found that mRNA for CYP2D6 waspredominantly expressed in the right ventricle. A strongcorrelation between tissue-specific gene expression andenzyme activity was also found.Monohydroxylation of the antianginal agent perhexiline is

almost exclusively catalysed by CYP2D6 with activitiesbeing about 100-fold lower in CYP2D6 PMs than in EMs.126¥

Perhexiline has a concentration-related hepatotoxicity andperipheral neuropathy and determination of the CYP2D6genotype will predict dose requirements and reduce the riskof perhexiline concentration-related toxicity.127¥

In a retrospective study, Wuttke et al.128¥ identified 24patients treated with metoprolol who had experiencedpronounced adverse effects. Genotyping revealed a five-foldhigher frequency of PMs in this group ¤38%¥ as comparedto the control population. As many of the drugs used totreat cardiovascular diseases have a wide therapeuticwindow, the impact of CYP2D6 polymorphism becomesless significant. As expected, CYP2D6 genotype-phenotypecorrelates with differences in metoprolol pharmacokineticswith 30-fold variability in area under the curve ¤AUC¥among EMs. However, there was no association betweenvariable pharmacokinetics or CYP2D6 genotype and Ç-blocker-induced adverse effects or efficacy.129¥

Genetic polymorphism of CYP2D6 and tamoxifen:Genetic polymorphisms of CYP2D6 have been reported asthe major cause of variation in the metabolism of tamoxifenthat leads to adverse effects or lack of therapeutic efficacy.The US Food and Drug Administration ¤FDA¥ advisorycommittee has recommended labeling changes to indicatethat post-menopausal estrogen receptor ¤ER¥ positive breastcancer patients who are taking adjuvant tamoxifen and arehomozygous CYP2D6*4/*4 have significantly decreasedrelapse-free survival compared to those with the hetero-zygous or homozygous wild type of CYP2D6.130,131¥ Howeverthe FDA has not recommended routine testing of all womenon tamoxifen for risk stratification. In addition, there wereno comments on the impact of several variants such asCYP2D6 *5,*10, and*41 and ethnic variation. Wide inter-patient variations in responses to tamoxifen have beenobserved across populations where administration of thesame dose of this drug results in a range of outcomes whichinclude adverse events or therapeutic failure. AmongCaucasians, tamoxifen-treated patients carrying the hetero-zygous and homozygous CYP2D6*4 had a significantlyincreased risk of recurrence of breast cancer, shorterrelapse-free periods and worse event-free survival rates

compared with carriers of functional alleles.130,131¥ A recentstudy among breast cancer patients with CYP2D6*10/*10 inAsians has shown that the steady state plasma levels of4-hydroxytamoxifen and endoxifen were significantly lower.In addition, breast cancer patients with CYP2D6*10/*10had significantly shorter median time to disease progressioncompared to patients who were homozygous wild-type orheterozygotes.132®134¥ Furthermore, breast cancer patientswho received adjuvant tamoxifen therapy revealed worsetherapy outcomes in patients with the CYP2D6*10/*10genotype and significantly higher incidence of recurrencewithin 10 years after the operation.133,135¥ In a Japanesestudy, women who had the CYP2D6*10/*10 genotype hada significantly higher incidence of recurrence within 10years compared to women with the wild type genotype¤CYP2D6*1/*1¥. Patients with genotype CYP2D6*10/*10showed shorter recurrence-free survival relative to the wildtype ¤CYP2D6*1/*1¥. The results of a Chinese study of 152women with breast cancer receiving tamoxifen were alsosupportive.135¥ The study observed that the serum levels of4-hydroxy-tamoxifen were reduced in patients bearingthe homozygous CYP2D6*10/*10 genotype relative to thewild type. They also observed that disease-free survival wasreduced 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 theCYP2D6*4/*4 genotype. The CYP2D6*4 polymorphismaffects breast cancer survival in tamoxifen users.137¥ Inmulti-variate models that adjusted for age, race/ethnicity,educational status, method of referral into the study,and prior knowledge of CYP2D6 testing, the patientsöCYP2D6 genotype was found to be the only significantfactor that predicted a change in the choice of hormonaltherapy.137¥

Kiyotani et al.138¥ evaluated the usefulness of knowledgeof CYP2D6 genotypes in 98 Japanese breast cancer patientswho had been taking 20mg of tamoxifen daily as anadjuvant setting. For the patients who had one or nonormal allele of CYP2D6, dosages of tamoxifen wereincreased to 30 and 40mg/day, respectively. Dose adjust-ment was found to be appropriate in the patients carryingthe CYP2D6*10 allele to maintain an effective endoxifenlevel. These findings are important to predict the effec-tiveness and resistance of tamoxifen therapy among breastcancer patients. These lines of evidence also imply that pre-genotyping of CYP2D6 intermediate metaboliser is impor-tant before prescribing tamoxifen. These results confirmedthe findings of previous studies and support FDArecommendation to perform pre-genotyping in patientsbefore the choice of therapy is determined in breast cancerpatients. In contrast, two studies from Japan showed thatthe CYP2D6*10/*10 genotype was unlikely to have anyclinical significance on breast cancer patients receivingadjuvant tamoxifen.139,140¥



CYP2D6 And Drug Interactionsand Clinical Implication

As CYP2D6 plays an important role in the metabolism ofat least 25% of the marketed drugs, there are possible issuesof drug interactions in vivo which are of clinical significance.Substrates with a high affinity bind strongly to CYP2D6 andwould result in inhibition of the metabolism of othercompounds which have lower affinity. Consequently, druginteractions occur in EMs, but not in PMs as they do not haveCYP2D6 enzymes to compete for. Another issue thatrequires attention is phenocopying, whereby an EM would bephenotypically poor if he was concurrently prescribed astrong inhibitor of CYP2D6. The first pass metabolism of thesubstrate might be inhibited and the rate of eliminationprolonged resulting in higher plasma concentration andtoxicity. On the other hand, inhibition of metabolism byCYP2D6 causes lack of therapeutic response when thepharmacological action is dependent on the transformation ofpro-drugs to active metabolites. Since CYP2D6 is notinducible, drug interactions due to enzyme induction are veryunlikely 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 whenselective serotonin reuptake inhibitors ¤SSRIs¥ are used toreduce hot flushes in women with breast cancer, but resultsin decreased plasma concentrations of the active metaboliteendoxifen. Thus the use of the SSRIs that are potentCYP2D6 inhibitors ¤e.g., paroxetine and fluoxetine¥ con-currently with tamoxifen may be associated with pooreroutcomes and should be avoided as far as possible.141¥ TheNCCTG 89-30-52 trial analysed the co-prescription ofCYP2D6 inhibitors and CYP2D6 metaboliser status andconcluded that the clinical benefit of tamoxifen wassignificantly decreased in patients with decreased CYP2D6activity either due to the PM genotype or the concurrentuse of CYP2D6 inhibitors.142¥ In addition to drug-druginteraction, cautious use of herbal medicine should bepracticed to avoid drug-herb interactions. For example, thealkaloids protopine and allocryptopine in black cohoshwere identified as competitive CYP2D6 inhibitors and thusshould be used with caution in breast cancer patientstreated with tamoxifen.143¥ Similarly, concurrent use ofHypericum extract should be avoided in patients treatedwith SSRIs.144¥

In 2000 Hamelin et al. reported interaction of non-presription drugs with CYP2D6 substrates.123¥ There was a61% increment in the AUC of metoprolol when diphenhydr-amine was co-administered in EMs. A significant aggravationof metoprolol-related effects such as decrease in heart rate,systolic blood pressure, and Doppler-assessed aortic bloodflow was observed after administration of diphenhydramine.Even though metoprolol has a wide therapeutic window, theinteraction can be severe especially because many older

patients with multiple co-morbidities take both of thesedrugs simultaneously.

CYP2D6 and Disease Susceptibility

The CYP2D6 phenotype and genotype has been inves-tigated with respect to the risk of cancers and other diseases.Individuals who were EMs because of CYP2D6 had higherrisks of malignant processes as increased metabolism of oneor more agents in the diet or other environmental agents,mediated by CYP2D6, forms reactive intermediaries thatinfluence the initiation or promotion of cancer in varioustissues.145¥ It has been found that polymorphism at locithat encode carcinogen-metabolizing enzymes such ascytochrome P450, which catalyzes the detoxification ofcarcinogens, may determine susceptibility to cancer. Onthe other hand, PMs must be exposed longer to the toxiceffects of non-metabolised drugs and numerous otherfactors to have increased risks of cancers. The types ofcancer that were evaluated included melanoma, lung-,breast-, anogenital-, basal cell- aerodigestive tract-, oral-,prostate-, pancreatic- and bladder-cancer. Association wasobserved between the CYP2D6 gene and lung cancer,146¥

bladder cancer147¥ and oral cancer.148¥ London et al.149¥ foundthat the CYP2D6 genetic polymorphism is not a strong riskfactor for lung cancer. Smith et al.150¥ and Goetz et al.151¥

stated that CYP2D6 genotype is not the causal factor forbreast cancer. Meanwhile, reduced CYP2D6 activity ¤PM¥has been related to greater risk of leukemia and oralcancer.148¥ There is however a lack of consistency in theresults observed, and a clear distinction between the EM andPM phenotypes with regard to susceptibility to cancercannot be established.CYP2D6s are found in the brain and they are similar to

those found in the liver and thus studies have attemptedto associate their role with CNS disorder. Researchershypothesized that CYP2D6 may play an essential role in thebiological activity as it is expressed in the brain. In fact, twostudies have indicated a significant relationship betweenCYP2D6 and behavior, using psychological tests and thepresence of CYP2D6.152,153¥ It was shown that there was ahigher number carrying more than two active CYP2D6 genes¤gene duplication¥ among those who died of suicide ¤suicidecases¥, as compared with those who died of natural causes¤natural-death cases¥ ¤p © 0.007¥.154¥ It was suggested thatCYP2D6 transforms 5-methoxy tryptamine to serotonin inthe brain of suicide attempters.155¥ Several studies haveindicated serotonergic hypofunction in suicidal behavior.156¥

These studies suggest that CYP2D6 in the human brain isimportant for behavior.Interestingly, Pai et al.157¥ have provided evidence that a

common variant of the pseudogene CYP2D7 could beexpressed in an active form in human brain yielding afunctional enzyme that is active in the metabolism ofcodeine. Allelic variation at the CYP2D6 gene has beensuggested to be associated with CNS disorders, includ-



ing Parkinsonös disease ¤PD¥, Lewy body dementia andAlzheimerös.158¥ Poor CYP2D6 metabolisers were are athigher risk for PD due to their reduced ability to inactivatePD-causing neurotoxins. Patients with PD cases hadapproximately 40% lower CYP2D6 levels in the frontalcortex, cerebellum, and hippocampus.159¥

However, the CYP2D6 genotypes related disease risk areconflicting due to the small sample size and the heterogenousnature of the diseases, the sampling and nature of age-matching, and the polygenic nature of these diseases.160¥ Inaddition, the genotypes screened in each study maybe limited and not comprehensive enough to provideconclusive data.

Conclusion

CYP2D6 is highly polymorphic and heterogenous. Thetype and frequencies of alleles show ethnic specificities. Theclinical impact of genetic polymorphism of drug metabolismenzymes is higher in drugs with a narrow therapeuticwindow and only one metabolic pathway is involved withmore than 90% of the metabolism. Many of the drugs todayare designed to share more than one drug metabolizingenzyme. This would increase the market population assevere toxicity due to impaired functionality of one enzymewould be reduced. However, toxicity due to drug inter-action may occur due to phenocopying and special attentionis required. Thus far, pre-genotyping of CYP2D6 beforedrugs are prescribed is recommended for tamoxifen,antidepressants and antipsychotics to identify those specialpatients who may need to have the dosage adjusted. InCaucasians, the risk of adverse effects due to poormetabolism would be higher than in Asians.Asians have a lower capability to metabolise CYP2D6

substrates but as most of the CYP2D6 substrates do not havenarrow therapeutic windows, the clinical impact is lessobvious. However, if the drugs are for chronic dosing,accumulation may occur and result in toxicity.

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http://dx.doi.org/10.2165/00023210-199605030-00006

http://dx.doi.org/10.2165/00023210-199605030-00006










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Pharmacogenomics of CYP2D6: Molecular Genetics ... Pharmacogenomics of CYP2D6: Molecular Genetics, Interethnic Differences and Clinical Importance Lay Kek TEH1,* and Leif BERTILSSON2