CYP2D6

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 is considerable variability in its expression in the liver.

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 no CYP2D6 function
ultrarapid metaboliser - these subjects have multiple copies of the CYP2D6 gene expressed, and therefore greater-than-normal CYP2D6 function

The patients' 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. Genotype assays do not, however, give information on the phenotype and therefore cannot identify ultrarapid metabolisers.

Genetic basis of variability

The genetic basis for extensive and poor metaboliser variability is the CYP2D6 allele. 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
CYP2D61*	normal
CYP2D63*	none
CYP2D64*	none
CYP2D65*	none
CYP2D69*	decreased
CYP2D610*	decreased
CYP2D617*	decreased

Ethnic factors in variability

Furthermore ethnicity is a factor in the occurrence of CYP2D6 variability. The prevalence of CYP2D6 poor metabolisers is approximately 6-10% amongst Caucasian populations, but is lower in most other ethnic groups such as Asians (2%) . In African Americans, however, the frequency of poor metabolizers is greater than for Caucasians (1.6% vs. 0.44%) . 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 - appoximately 10% of Caucasians appear to have the non-functional CYP2D6*4 allele while approximately 50% of Asians possess the CYP2D6*10 allele, which should produce decreased CYP2D6 function; however this still appears to be within the normal range and are still grouped as extensive metabolisers.

CYP2D6 Ligands

Where classes of agents are listed, there may be exceptions within the class.

Selected inducers, inhibitors and substrates of CYP2D6¹
Type	Agent
inducers	dexamethasone, rifampicin
inhibitors	amiodarone, antihistamines (chlorphenamine, diphenhydramine, etc), antipsychotics (chlorpromazine, haloperidol, etc), bupropion, celecoxib, cimetidine, clomipramine, cocaine, doxorubicin, metoclopramide, methadone, moclobemide, quinidine, ranitidine, ritonavir, SSRIs (citalopram, fluoxetine, etc), terbinafine
substrates	amphetamine, antipsychotics (haloperidol, risperidone, etc), β-blockers (carvedilol, metoprolol, etc), chlorphenamine, Class I antiarrhythmics (lidocaine, flecainide, etc), debrisoquine, dextromethorphan, metoclopramide, ondansetron, opioids (codeine, tramadol, etc), SSRIs (fluoxetine, paroxetine, etc), tamoxifen, tricyclic antidepressants (imipramine, amitriptyline, etc), venlafaxine, vinca alkaloids (vincristine, etc)
Notes:

References

Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians. Pharmacogenetics 1998 Aug; 8(4): 325-33. PMID 9731719
Fulltext options (subscription and/or purchase may or may not be required) List of Library Holdings Worldwide
Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 1997 Jun; 7(3): 187-91 PMID 9241658
Australian Medicines Handbook (AMH) 2004. ISBN 0-9578521-4-2

External links

Flockhart Lab Cyp2D6 Substrates Page

Cytochrome P450 | EC 1.14.14