Download Pharmacogenomics of CYP2D6: Molecular Genetics, Interethnic

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. However, if the drugs are for chronic dosing,
accumulation may occur and result in toxicity.
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