Everything about Cyp2d6 totally explained
| Name = Cytochrome P450, family 2, subfamily D, polypeptide 6
| HGNCid = 2625
| Symbol = CYP2D6
| AltSymbols =; CYP2D; CYP2D@; P450C2D; CPD6; CYP2DL1; MGC120389; MGC120390; P450-DB1
| OMIM = 124030
| ECnumber =
| Homologene = 68036
| MGIid = 1929474
| GeneAtlas_image1 = PBB_GE_CYP2D6_207498_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_CYP2D6_215809_at_tn.png
| Function =
| Component =
| Process =
| Orthologs =
}}
Cytochrome P450 2D6 (CYP2D6), a member of the
cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of
xenobiotics in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the
CYPs, there's considerable variability in its expression in the liver. The gene is located near two cytochrome P450
pseudogenes on chromosome 22q13.1.
Alternatively spliced transcript variants encoding different
isoforms have been found for this gene.
Genotype/phenotype variability
CYP2D6 shows the largest
phenotypical variability amongst the CYPs, largely due to
genetic polymorphism. The
genotype accounts for normal, reduced and non-existent CYP2D6 function in subjects.
The CYP2D6 function in any particular subject may be described as one of the following:
- extensive metaboliser - these subjects have normal or reduced CYP2D6 function
- poor metaboliser - these subjects have little or no CYP2D6 function
- ultrarapid metaboliser - these subjects have multiple copies of the CYP2D6 gene expressed, and therefore greater-than-normal CYP2D6 function
A patient's CYP2D6 phenotype is often clinically determined via the administration of
debrisoquine (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine
metabolite (4-hydroxydebrisoquine). More recently, a "
DNA microarray" has been developed, known as the
AmpliChip, which allows the automated determination of a patient's CYP2D6 (or
CYP2C19) genotype.
Genetic basis of variability
The genetic basis for extensive and poor metaboliser variability is the
CYP2D6 allele, located on
chromosome 22. Subjects who possess certain allelic variants will show normal, decreased or no CYP2D6 function depending on the allele.
| CYP2D6 allele and enzyme activity (after Droll et al., 1998) |
| Allele |
CYP2D6 activity |
| CYP2D6*1 |
normal |
| CYP2D6*3 |
none |
| CYP2D6*4 |
none |
| CYP2D6*5 |
none |
| CYP2D6*9 |
decreased |
| CYP2D6*10 |
decreased |
| CYP2D6*17 |
decreased |
Ethnic factors in variability
Ethnicity is a factor in the occurrence of CYP2D6 variability. The prevalence of CYP2D6 poor metabolizers is approximately 6-10% amongst
white populations, but is lower in most other ethnic groups such as
Asians (2%). In
blacks, the frequency of poor metabolizers is greater than for whites. The occurrence of CYP2D6 ultrarapid metabolisers appears to be greater amongst
Middle Eastern and
North African populations.
This variability is accounted for by the differences in the prevalence of various
CYP2D6 alleles amongst the populations - approximately 10% of whites appear to have the non-functional CYP2D6*4 allele while approximately 50% of Asians possess the CYP2D6*10 allele'
|-
! Substrates !! Inhibitors !! Inducers
|- ignore="vertical-align: top;"
| Often mentioned:
beta-blockers
Class I antiarrhythmics
All tricyclic antidepressants, for example
Most SSRIs, for example
opioids
debrisoquine (antihypertensive)
dextromethorphan (antitussive)
venlafaxine (SNRI)
antipsychotics, for example
ondansetron (5-HT3 receptor antagonist)
Other:
alprenolol (beta-blocker)
mianserin (tetracyclic antidepressant)
phenformin (antidiabetic)
tropisetron (5-HT3 receptor antagonist)
amphetamine (in ADHD, narcolepsy)
chlorphenamine (antihistamine)
metoclopramide (dopamine antagonist)
tamoxifen (SERM)
vinca alkaloids (anti-mitotic, anti-microtubule)
|| Strong:
SSRIs
terbinafine (antifungal)
quinidine (class I antiarrhythmic agent)
unspecified:
amiodarone (antiarrhythmic)
antihistamine (H1-receptor antagonists)
antipsychotic
bupropion (antidepressant)
celecoxib (NSAID)
cimetidine (H2-receptor antagonist)
clomipramine (tricyclic antidepressant)
chloramphenicol (laevomycetin)
cocaine (stimulant)
doxorubicin (chemotherapeutic)
metoclopramide (antiemetic, prokinetic)
methadone (analgesic and anti-addictive)
moclobemide (antidepressant)
quinidine (Class I antiarrhythmic)
ranitidine (H2-receptor antagonist)
ranolazine (antianginal)
ritonavir (antiretroviral)
doxepin (tricyclic antidepressant, anxiolytic)
halofantrine (in malaria)
imipramine (tricyclic antidepressant)
levomepromazine (antipsychotic)
metoclopramide (antiemetic, prokinetic)
pimozide (antipsychotic)
thioridazine (antipsychotic)
||
Strong:
Piperidines and derivatives (pharmacokinetics modifiers)
carbamazepine
Unspecified:
dexamethasone (glucocorticoid)
rifampicin (bactericidal)
|-
|}
Further Information
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