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CYP2D6

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CYP2D6
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCYP2D6, CPD6, CYP2D, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, CYP2DL1, CYPIID6, P450-DB1, P450C2D, P450DB1, cytochrome P450 family 2 subfamily D member 6, Cytochrome P450 2D6
External IDsOMIM: 124030; MGI: 1929474; HomoloGene: 133550; GeneCards: CYP2D6; OMA:CYP2D6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1565

56448

Ensembl

ENSMUSG00000061740

UniProt

P10635

Q9JKY7

RefSeq (mRNA)

NM_000106
NM_001025161

NM_001163472
NM_019823

RefSeq (protein)

NP_000097
NP_001020332

NP_001156944
NP_062797

Location (UCSC)Chr 22: 42.13 – 42.13 MbChr 15: 82.25 – 82.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cytochrome P450 2D6 is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the CNS, including the substantia nigra.

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. In particular, CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, via the addition or removal of certain functional groups – specifically, hydroxylation, demethylation, and dealkylation – at various points along a substrate's core structure.[5] This enzyme also metabolizes several endogenous substances, such as hydroxytryptamines, neurosteroids, and both m-tyramine and p-tyramine which CYP2D6 metabolizes into dopamine in the brain and liver.[5][6]

There is considerable variation in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 substrates), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers). If a drug is metabolized too quickly, it may decrease the drug's efficacy while if the drug is metabolized too slowly, toxicity may result.[7] Hence the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.[8]

In addition, other drugs may function as inhibitors of CYP2D6 activity or inducers of CYP2D6 enzyme expression that will lead to decreased or increased CYP2D6 activity respectively. If such a drug is taken at the same time a second drug that is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a drug-drug interaction.[7]

Gene

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.[9]

Genotype/phenotype variability

CYP2D6 shows the largest phenotypical variability among the CYPs, largely due to genetic polymorphism. The genotype accounts for normal, reduced, and non-existent CYP2D6 function in subjects. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.[10] The CYP2D6 function in any particular subject may be described as one of the following:[11]

  • poor metabolizer – little or no CYP2D6 function
  • intermediate metabolizers – metabolize drugs at a rate somewhere between the poor and extensive metabolizers
  • extensive metabolizer – normal CYP2D6 function
  • ultrarapid metabolizer – multiple copies of the CYP2D6 gene are 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).[12]

The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects.[13]

Genetic basis of variability

The genetic basis for CYP2D6-mediated metabolic variability is the CYP2D6 allele, located on chromosome 22. Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6 function, depending on the allele. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.[10]

CYP2D6 enzyme activity for selected alles[14][15]
Allele CYP2D6 activity
CYP2D6*1 normal
CYP2D6*2 normal
CYP2D6*3 none
CYP2D6*4 none
CYP2D6*5 none
CYP2D6*6 none
CYP2D6*7 none
CYP2D6*8 none
CYP2D6*9 decreased
CYP2D6*10 decreased
CYP2D6*11 none
CYP2D6*12 none
CYP2D6*13 none
CYP2D6*14 none
CYP2D6*15 none
CYP2D6*17 decreased
CYP2D6*19 none
CYP2D6*20 none
CYP2D6*21 none
CYP2D6*29 decreased
CYP2D6*31 none
CYP2D6*38 none
CYP2D6*40 none
CYP2D6*41 decreased
CYP2D6*42 none
CYP2D6*68 none
CYP2D6*92 none
CYP2D6*100 none
CYP2D6*101 none
CYP2D6 duplication increased

Ethnic factors in variability

Race is a factor in the occurrence of CYP2D6 variability. The prevalence of CYP2D6 poor metabolizers is approximately 6–10% in white populations, but is lower in most other ethnic groups such as Asians (2%).[16] In African-Americans, the frequency of poor metabolizers is greater than for whites.[17] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.[18]

Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent.[19]

This variability is accounted for by the differences in the prevalence of various CYP2D6 alleles among the populations–approximately 10% of whites are intermediate metabolizers, due to decreased CYP2D6 function, because they appear to have the non-functional CYP2D6*4 allele,[14] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.[14]

Ligands

Following is a table of selected substrates, inducers and inhibitors of CYP2D6. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2D6 can be classified by their potency, such as:

  • Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.[20]
  • Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.[20]
  • Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.[20]
Selected inducers, inhibitors and substrates of CYP2D6
Substrates
↑ = bioactivation by CYP2D6		 Inhibitors Inducers

Strong

Moderate

Weak

Unspecified potency

Strong

Unspecified potency

Dopamine biosynthesis

Biosynthetic pathways for catecholamines and trace amines in the human brain[34][35][36]
The image above contains clickable links
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine. It is well established that dopamine is produced from L-tyrosine via L-dopa; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from L-tyrosine via p-tyramine.[36] Similarly, CYP2D6 also metabolizes m-tyramine into dopamine.[36]


References

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000061740 – Ensembl, May 2017
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  22. ^ a b PHARMACOGENETICS AND PHARMACOGENOMICS. J. Steven Leeder PharmD, PhD Pediatric Clinics of North America - Volume 48, Issue 3 (June 2001). doi:10.1016/S0031-3955%2805%2970338-2.
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  27. ^ http://www.drugs.com/pro/citalopram-oral-solution.html. Retrieved 5 February 2016. {{cite web}}: Missing or empty |title= (help)
  28. ^ http://www.drugs.com/pro/escitalopram-oral-solution.html. Retrieved 5 February 2016. {{cite web}}: Missing or empty |title= (help)
  29. ^ http://www.gjpsy.uni-goettingen.de/gjp-article-nevels.pdf
  30. ^ a b c d e FASS, The Swedish official drug catalog > Kodein Recip Last reviewed 2008-04-08
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  32. ^ He N, Zhang WQ, Shockley D, Edeki T (February 2002). "Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes". Eur. J. Clin. Pharmacol. 57 (12): 847–51. doi:10.1007/s00228-001-0399-0. PMID 11936702.
  33. ^ Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2011). "Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6". Drug Metab Dispos. 39 (11): 2049–56. doi:10.1124/dmd.111.041384. PMID 21821735.
  34. ^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
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  36. ^ a b c Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". European Journal of Pharmacology. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.

Further reading

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