CYP2D6

CYP2D6
Available structures
PDB	Human UniProt search: PDBe RCSB
List of PDB id codes
	2F9Q, 3QM4, 3TBG, 3TDA, 4WNT, 4WNU, 4WNV, 4WNW, 4XRY, 4XRZ
Identifiers
Aliases	CYP2D6, CPD6, CYP2D, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, CYP2DL1, CYPIID6, P450-DB1, P450C2D, P450DB1, cytochrome P450 family 2 subfamily D member 6, Cytochrome P450 2D6
External IDs	OMIM: 124030 HomoloGene: 133550 GeneCards: CYP2D6
Targeted by Drug
	raubasine
Gene ontology
Molecular function	• iron ion binding; • metal ion binding; • monooxygenase activity; • heme binding; • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; • drug binding; • oxidoreductase activity; • aromatase activity; • oxygen binding; • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen;
Cellular component	• organelle membrane; • endoplasmic reticulum membrane; • membrane; • intracellular membrane-bounded organelle; • endoplasmic reticulum; • mitochondrion;
Biological process	• steroid metabolic process; • alkaloid metabolic process; • coumarin metabolic process; • lipid metabolic process; • isoquinoline alkaloid metabolic process; • alkaloid catabolic process; • oxidative demethylation; • drug catabolic process; • heterocycle metabolic process; • negative regulation of binding; • drug metabolic process; • monoterpenoid metabolic process; • xenobiotic metabolic process; • oxidation-reduction process; • arachidonic acid metabolic process; • negative regulation of cellular organofluorine metabolic process;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ;
	More reference expression data
Orthologs
	1565
	n/a
	n/a
	n/a
	P10635
	n/a
	NM_000106; NM_001025161
	n/a
	NP_000097; NP_001020332
	n/a
	Wikidata
View/Edit Human

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.^[3] 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.^[3]^[4]

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.^[5] 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.^[6]

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 as 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.^[5]

Gene[edit]

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.^[7]

Genotype/phenotype variability[edit]

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.^[8] The CYP2D6 function in any particular subject may be described as one of the following:^[9]

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).^[10]

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.^[11]

Genetic basis of variability[edit]

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.^[8]

CYP2D6 enzyme activity for selected alles^[12]^[13]
Allele	CYP2D6 activity
CYP2D61*	normal
CYP2D62*	normal
CYP2D63*	none
CYP2D64*	none
CYP2D65*	none
CYP2D66*	none
CYP2D67*	none
CYP2D68*	none
CYP2D69*	decreased
CYP2D610*	decreased
CYP2D611*	none
CYP2D612*	none
CYP2D613*	none
CYP2D614*	none
CYP2D615*	none
CYP2D617*	decreased
CYP2D619*	none
CYP2D620*	none
CYP2D621*	none
CYP2D629*	decreased
CYP2D631*	none
CYP2D638*	none
CYP2D640*	none
CYP2D641*	decreased
CYP2D642*	none
CYP2D668*	none
CYP2D692*	none
CYP2D6100*	none
CYP2D6101*	none
CYP2D6 duplication	increased

Ethnic factors in variability[edit]

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%).^[14] In African-Americans, the frequency of poor metabolizers is greater than for whites.^[15] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.^[16]

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.^[17]

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,^[12] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.^[12]

Ligands[edit]

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.^[18]
Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.^[18]
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.^[18]

**Selected inducers, inhibitors and substrates of CYP2D6**
Substrates ↑ = bioactivation by CYP2D6	Inhibitors	Inducers
All^[19] tricyclic antidepressants, e.g. imipramine^[18] amitriptyline^[18] etc. Most^[19] SSRIs (antidepressant), e.g. fluoxetine^[18] paroxetine^[18] fluvoxamine^[18] venlafaxine^[18]^[19] (SNRI antidepressant) duloxetine^[18] (SNRI) mianserin^[19] (tetracyclic antidepressant) mirtazapine^[19] (antidepressant) opioids codeine^[18]^[19] ↑^[20] [into morphine] tramadol^[18]^[19] ↑ ^[20] [into O-desmethyltramadol] O-desmethyltramadol ↑ [into N,O-didesmethyltramadol] N-desmethyltramadol [inactive] ↑ [into N,O-didesmethyltramadol] oxycodone ^[18] hydrocodone ↑^[21] [into hydromorphone] tapentadol antipsychotics, e.g. haloperidol^[18]^[19] risperidone^[18]^[19] perphenazine^[18]^[19] thioridazine^[18]^[19] zuclopenthixol^[18]^[19] iloperidone^[18]^[19] aripiprazole^[18]^[19] chlorpromazine^[18]^[19] levomepromazine^[19] remoxipride^[19] minaprine^[18] (RIMA antidepressant) tamoxifen^[18]^[19] ↑^[22] into hydroxytamoxifen (SERM) beta-blockers metoprolol^[18]^[19] timolol^[18]^[19] alprenolol^[18]^[19] carvedilol^[18] bufuralol^[18] nebivolol^[18] propranolol^[18] debrisoquine^[18] (antihypertensive) Class I antiarrhythmics flecainide^[18]^[19] propafenone^[18]^[19] encainide^[18]^[19] mexiletine^[18]^[19] lidocaine (mainly by 3A4)^[18] sparteine^[18] ondansetron^[18]^[19] (antiemetic) donepezil^[18]^[19] (acetylcholinesterase inhibitor) phenformin^[18]^[19] (antidiabetic) tropisetron^[19] (5-HT3 receptor antagonist) stimulants amphetamine^[18] methoxyamphetamine^[18] dextromethamphetamine^[18] atomoxetine^[18] chlorphenamine^[18] (antihistamine) dexfenfluramine^[18] (serotoninergic anorectic) dextromethorphan^[18] (antitussive) [into dextrorphan] metoclopramide^[18] (dopamine antagonist) perhexiline^[18] (antianginal agent) phenacetin^[18] (analgesic) promethazine^[18] (antihistamine antiemetic)	Strong Certain SSRIs fluoxetine^[18]^[19] paroxetine^[18]^[19] bupropion^[18]^[23] (non-SSRI antidepressant) quinidine^[18]^[19] (class I antiarrhythmic agent) cinacalcet^[18] (calcimimetic) ritonavir^[19] (antiretroviral) Moderate sertraline^[18] (SSRI) duloxetine^[18] (SNRI) terbinafine^[18] (antifungal) Weak amiodarone^[18] (antiarrhythmic) buprenorphine^[24] (in opioid addiction) cimetidine^[18] (H2-receptor antagonist) citalopram^[18]^[25] (SSRI) escitalopram^[18]^[26] (SSRI) methylphenidate ^[27] Unspecified potency antipsychotics haloperidol^[28]^[18] perphenazine^[18]^[28] thioridazine^[28] zuclopenthixol^[28] risperidone^[28] chlorpromazine^[18] hyperforin (St. Johns Wort)^[29] antihistamines (H1-receptor antagonists) * promethazine^[30](antipsychotic) chlorphenamine^[18] diphenhydramine^[18] hydroxyzine^[18] tripelennamine^[18] clemastine^[18] (antihistamine and anticholinergic) celecoxib^[18] (NSAID) clomipramine^[18] (tricyclic antidepressant) cocaine^[18] (stimulant) doxorubicin^[18] (chemotherapeutic) metoclopramide^[18] (antiemetic, prokinetic) methadone^[18] (analgesic and anti-addictive) moclobemide^[18] (antidepressant) doxepin^[18] (tricyclic antidepressant, anxiolytic) halofantrine^[18] (in malaria) levomepromazine^[18] (antipsychotic) mibefradil^[18] (calcium channel blocker) midodrine^[18] (α₁ agonist) ticlopidine^[18] (antiplatelet) cannabidiol^[31] (phytocannabinoid)	Strong glutethimide (hypnotic sedative) Unspecified potency dexamethasone^[18] (glucocorticoid) rifampicin^[18] (bactericidal) haloperidol^[32] (typical antipsychotic)

Dopamine biosynthesis[edit]

Biosynthetic pathways for catecholamines and trace amines in the human brain^[33]^[34]^[35]

N-Methylphenethylamine

primary
pathway

brain
CYP2D6

minor
pathway

COMT

DBH

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.^[35] Similarly, CYP2D6 also metabolizes m-tyramine into dopamine.^[35]

References[edit]

^ "Drugs that physically interact with Cytochrome P450 family 2 subfamily D member 6 view/edit references on wikidata".
^ "Human PubMed Reference:".
^ ^a ^b Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF (2009). "New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme". Drug Metab. Rev. 41 (4): 573–643. doi:10.1080/03602530903118729. PMID 19645588.
^ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.
^ ^a ^b Teh LK, Bertilsson L (2012). "Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance". Drug Metab. Pharmacokinet. 27 (1): 55–67. doi:10.2133/dmpk.DMPK-11-RV-121. PMID 22185816.
^ Walko CM, McLeod H (April 2012). "Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment". Pharmacogenomics. 13 (6): 691–7. doi:10.2217/pgs.12.27. PMID 22515611.
^ "Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6".
^ ^a ^b Ostille DO, Warren AM, Kulkarni J (Jan 2014). "The role of pharmacogenomic testing in psychiatry". Aust New Zealand J Psychiatry. 48 (8): 778. doi:10.1177/0004867413520050. PMID 24413808.
^ Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A (February 2002). "Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs". Br J Clin Pharmacol. 53 (2): 111–22. doi:10.1046/j.0306-5251.2001.01548.x. PMC 1874287. PMID 11851634.
^ Llerena A, Dorado P, Peñas-Lledó EM (January 2009). "Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity". Pharmacogenomics. 10 (1): 17–28. doi:10.2217/14622416.10.1.17. PMID 19102711.
^ Lynch T, Price A (August 2007). "The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects". Am Fam Physician. 76 (3): 391–6. PMID 17708140.
^ ^a ^b ^c Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF (1998). "Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians". Pharmacogenetics. 8 (4): 325–33. doi:10.1097/00008571-199808000-00006. PMID 9731719.
^ "CYP2D6 allele nomenclature". Retrieved 5 February 2016.
^ Australian Medicines Handbook (AMH) 2004. ISBN 0-9578521-4-2
^ Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002). "Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans". Clin. Pharmacol. Ther. 72 (1): 76–89. doi:10.1067/mcp.2002.125783. PMID 12152006.
^ McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M (June 1997). "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians". Pharmacogenetics. 7 (3): 187–91. doi:10.1097/00008571-199706000-00003. PMID 9241658.
^ Bradford LD (2002). "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants". Pharmacogenomics. 3 (2): 229–43. doi:10.1517/14622416.3.2.229. PMID 11972444.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al ^am ^an ^ao ^ap ^aq ^ar ^as ^at ^au ^av ^aw ^ax ^ay ^az ^ba ^bb ^bc ^bd ^be ^bf ^bg ^bh ^bi ^bj ^bk ^bl ^bm ^bn ^bo ^bp ^bq ^br ^bs ^bt ^bu ^bv ^bw ^bx ^by ^bz ^ca ^cb ^cc ^cd ^ce ^cf ^cg ^ch Flockhart DA (2007). "Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table". Indiana University School of Medicine. Retrieved on July 2011
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare), retrieved July 2011
^ ^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.
^ "Hydrocodone". Drugbank. Retrieved 14 June 2011.
^ Hoskins JM, Carey LA, McLeod HL (August 2009). "CYP2D6 and tamoxifen: DNA matters in breast cancer". Nat. Rev. Cancer. 9 (8): 576–86. doi:10.1038/nrc2683. PMID 19629072.
^ Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE (2005). "Inhibition of CYP2D6 activity by bupropion". J Clin Psychopharmacol. 25 (3): 226–9. doi:10.1097/01.jcp.0000162805.46453.e3. PMID 15876900.
^ Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metab. Dispos. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210.
^ http://www.drugs.com/pro/citalopram-oral-solution.html. Retrieved 5 February 2016. Missing or empty |title= (help)
^ http://www.drugs.com/pro/escitalopram-oral-solution.html. Retrieved 5 February 2016. Missing or empty |title= (help)
^ http://www.gjpsy.uni-goettingen.de/gjp-article-nevels.pdf^{[full citation needed]}
^ ^a ^b ^c ^d ^e FASS, The Swedish official drug catalog > Kodein Recip Last reviewed 2008-04-08
^ Foster BC, Sockovie ER, Vandenhoek S, Bellefeuille N, Drouin CE, Krantis A, Budzinski JW, Livesey J, and Arnason JT (2004). "In Vitro Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein". Pharmaceutical Biology. 42 (2): 159–169. doi:10.1080/13880200490512034.
^ 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.
^ 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.
^ Kudo S, Ishizaki T (1999). "Pharmacokinetics of haloperidol: an update". Clinical Pharmacokinetics. 37 (6): 435–56. doi:10.2165/00003088-199937060-00001. PMID 10628896.
^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
^ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375.
^ ^a ^b ^c Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199. The highest level of brain CYP2D activity was found in the substantia nigra ... The in vitro and in vivo studies have shown the contribution of the alternative CYP2D-mediated dopamine synthesis to the concentration of this neurotransmitter although the classic biosynthetic route to dopamine from tyrosine is active. ... Tyramine levels are especially high in the basal ganglia and limbic system, which are thought to be related to individual behavior and emotion (Yu et al., 2003c). ... Rat CYP2D isoforms (2D2/2D4/2D18) are less efficient than human CYP2D6 for the generation of dopamine from p-tyramine. The K_m values of the CYP2D isoforms are as follows: CYP2D6 (87–121 μm) ≈ CYP2D2 ≈ CYP2D18 > CYP2D4 (256 μm) for m-tyramine and CYP2D4 (433 μm) > CYP2D2 ≈ CYP2D6 > CYP2D18 (688 μm) for p-tyramine

External links[edit]

[1] "Drugs that physically interact with Cytochrome P450 family 2 subfamily D member 6 view/edit references on wikidata".

[2] "Human PubMed Reference:".

[pmid19645588-3] Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF (2009). "New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme". Drug Metab. Rev. 41 (4): 573–643. doi:10.1080/03602530903118729. PMID 19645588.

[Brain_CYP2D6-4] Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.

[pmid22185816-5] Teh LK, Bertilsson L (2012). "Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance". Drug Metab. Pharmacokinet. 27 (1): 55–67. doi:10.2133/dmpk.DMPK-11-RV-121. PMID 22185816.

[pmid22515611-6] Walko CM, McLeod H (April 2012). "Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment". Pharmacogenomics. 13 (6): 691–7. doi:10.2217/pgs.12.27. PMID 22515611.

[7] "Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6".

[PMID24413808-8] Ostille DO, Warren AM, Kulkarni J (Jan 2014). "The role of pharmacogenomic testing in psychiatry". Aust New Zealand J Psychiatry. 48 (8): 778. doi:10.1177/0004867413520050. PMID 24413808.

[pmid11851634-9] Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A (February 2002). "Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs". Br J Clin Pharmacol. 53 (2): 111–22. doi:10.1046/j.0306-5251.2001.01548.x. PMC 1874287. PMID 11851634.

[pmid19102711-10] Llerena A, Dorado P, Peñas-Lledó EM (January 2009). "Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity". Pharmacogenomics. 10 (1): 17–28. doi:10.2217/14622416.10.1.17. PMID 19102711.

[pmid17708140-11] Lynch T, Price A (August 2007). "The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects". Am Fam Physician. 76 (3): 391–6. PMID 17708140.

[Droll_1998-12] Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF (1998). "Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians". Pharmacogenetics. 8 (4): 325–33. doi:10.1097/00008571-199808000-00006. PMID 9731719.

[13] "CYP2D6 allele nomenclature". Retrieved 5 February 2016.

[14] Australian Medicines Handbook (AMH) 2004. ISBN 0-9578521-4-2

[15] Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002). "Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans". Clin. Pharmacol. Ther. 72 (1): 76–89. doi:10.1067/mcp.2002.125783. PMID 12152006.

[pmid9241658-16] McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M (June 1997). "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians". Pharmacogenetics. 7 (3): 187–91. doi:10.1097/00008571-199706000-00003. PMID 9241658.

[pmid11972444-17] Bradford LD (2002). "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants". Pharmacogenomics. 3 (2): 229–43. doi:10.1517/14622416.3.2.229. PMID 11972444.

[Flockhart-18] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al ^am ^an ^ao ^ap ^aq ^ar ^as ^at ^au ^av ^aw ^ax ^ay ^az ^ba ^bb ^bc ^bd ^be ^bf ^bg ^bh ^bi ^bj ^bk ^bl ^bm ^bn ^bo ^bp ^bq ^br ^bs ^bt ^bu ^bv ^bw ^bx ^by ^bz ^ca ^cb ^cc ^cd ^ce ^cf ^cg ^ch Flockhart DA (2007). "Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table". Indiana University School of Medicine. Retrieved on July 2011

[FASS-19] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare), retrieved July 2011

[Leeder-20] 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.

[21] "Hydrocodone". Drugbank. Retrieved 14 June 2011.

[pmid19629072-22] Hoskins JM, Carey LA, McLeod HL (August 2009). "CYP2D6 and tamoxifen: DNA matters in breast cancer". Nat. Rev. Cancer. 9 (8): 576–86. doi:10.1038/nrc2683. PMID 19629072.

[pmid15876900-23] Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE (2005). "Inhibition of CYP2D6 activity by bupropion". J Clin Psychopharmacol. 25 (3): 226–9. doi:10.1097/01.jcp.0000162805.46453.e3. PMID 15876900.

[pmid12756210-24] Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metab. Dispos. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210.

[25] ttp://www.drugs.com/pro/citalopram-oral-solution.html. Retrieved 5 February 2016. Missing or empty |title= (help)

[26] ttp://www.drugs.com/pro/escitalopram-oral-solution.html. Retrieved 5 February 2016. Missing or empty |title= (help)

[27] ttp://www.gjpsy.uni-goettingen.de/gjp-article-nevels.pdf^{[full citation needed]}

[fass-codeine-28] FASS, The Swedish official drug catalog > Kodein Recip Last reviewed 2008-04-08

[29] Foster BC, Sockovie ER, Vandenhoek S, Bellefeuille N, Drouin CE, Krantis A, Budzinski JW, Livesey J, and Arnason JT (2004). "In Vitro Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein". Pharmaceutical Biology. 42 (2): 159–169. doi:10.1080/13880200490512034.

[pmid11936702-30] 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.

[pmid21821735-31] 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.

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[CYP2D6_tyramine-dopamine_metabolism-35] Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199. The highest level of brain CYP2D activity was found in the substantia nigra ... The in vitro and in vivo studies have shown the contribution of the alternative CYP2D-mediated dopamine synthesis to the concentration of this neurotransmitter although the classic biosynthetic route to dopamine from tyrosine is active. ... Tyramine levels are especially high in the basal ganglia and limbic system, which are thought to be related to individual behavior and emotion (Yu et al., 2003c). ... Rat CYP2D isoforms (2D2/2D4/2D18) are less efficient than human CYP2D6 for the generation of dopamine from p-tyramine. The K_m values of the CYP2D isoforms are as follows: CYP2D6 (87–121 μm) ≈ CYP2D2 ≈ CYP2D18 > CYP2D4 (256 μm) for m-tyramine and CYP2D4 (433 μm) > CYP2D2 ≈ CYP2D6 > CYP2D18 (688 μm) for p-tyramine

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v t e Cytochromes, oxygenases: cytochrome P450 (EC 1.14)

CYP1	A1 A2 B1

CYP2	A6 A7 A13 B6 C8 C9 C18 C19 D6 E1 F1 J2 R1 S1 U1 W1

CYP3 (CYP3A)	A4 A5 A7 A43

CYP4	A11 A22 B1 F2 F3 F8 F11 F12 F22 V2 X1 Z1

CYP5-20	CYP5 (A1) CYP7 (A1, B1) CYP8 (A1, B1) CYP11 (A1, B1, B2) CYP17 (A1) CYP19 (A1) CYP20 (A1)

CYP21-51	CYP21 (A2) CYP24 (A1) CYP26 (A1, B1, C1) CYP27 (A1, B1, C1) CYP39 (A1) CYP46 (A1) CYP51 (A1)

v t e Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14)

1.14.11: 2-oxoglutarate	Prolyl hydroxylase Lysyl hydroxylase

1.14.13: NADH or NADPH	Flavin-containing monooxygenase FMO1 FMO2 FMO3 FMO4 FMO5 Nitric oxide synthase NOS1 NOS2 NOS3 Cholesterol 7 alpha-hydroxylase Methane monooxygenase 3A4 Lanosterol 14 alpha-demethylase 24-hydroxycholesterol 7α-hydroxylase

1.14.14: reduced flavin or flavoprotein	19A1 2D6 2E1

1.14.15: reduced iron-sulfur protein	11B1 11B2 11A1

1.14.16: reduced pteridine (BH4 dependent)	Phenylalanine hydroxylase Tyrosine hydroxylase Tryptophan hydroxylase

1.14.17: reduced ascorbate	Dopamine beta-hydroxylase

1.14.18-19: other	Tyrosinase Stearoyl-CoA desaturase-1

1.14.99 - miscellaneous	Cyclooxygenase Heme oxygenase (HMOX1) Squalene monooxygenase 17A1 21A2

v t e Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

CYP2D6

Contents

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