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{{Infobox_gene}}
{{Short description|Human cytochrome P450 enzyme}}
{{DISPLAYTITLE:CYP2D6}}


'''Cytochrome P450 2D6''' ('''CYP2D6''') 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 [[central nervous system]], including the [[substantia nigra]].
==Overview==
'''CYP2D6''' (Cytochrome P450 2D6) is an important enzyme in the [[cytochrome P450]] superfamily, which is involved in the metabolism of many drugs and xenobiotics in the body. It is encoded by the '''CYP2D6''' gene located on chromosome 22q13.1. This enzyme is responsible for the oxidative metabolism of approximately 25% of all clinically used medications, including antidepressants, antipsychotics, beta-blockers, and opioids.


CYP2D6, a member of the [[cytochrome P450]] mixed-function oxidase system, is one of the most important enzymes involved in the [[metabolism]] of [[xenobiotic]]s in the body. In particular, CYP2D6 is responsible for the metabolism and [[clearance (medicine)|elimination]] of approximately 25% of clinically used drugs, via the addition or removal of certain [[functional group]]s&nbsp;– specifically, [[hydroxylation]], [[demethylation]], and [[dealkylation]].<ref name="pmid19645588">{{cite journal | vauthors = Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF | title = New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme | journal = Drug Metabolism Reviews | volume = 41 | issue = 4 | pages = 573–643 | year = 2009 | pmid = 19645588 | doi = 10.1080/03602530903118729 }}</ref>  CYP2D6 also activates some [[prodrug]]s. This enzyme also metabolizes several endogenous substances, such as [[serotonin|hydroxytryptamines]], [[neurosteroid]]s, and both [[m-tyramine|''m''-tyramine]] and [[tyramine|''p''-tyramine]] which CYP2D6 metabolizes into [[dopamine]] in the brain and liver.<ref name="pmid19645588"/><ref name="Brain CYP2D6">{{cite journal | vauthors = Wang X, Li J, Dong G, Yue J | title = The endogenous substrates of brain CYP2D | journal = European Journal of Pharmacology | volume = 724 | pages = 211–8 | date = February 2014 | pmid = 24374199 | doi = 10.1016/j.ejphar.2013.12.025 }}</ref>
==Function==
CYP2D6 is primarily expressed in the [[liver]], where it plays a crucial role in the [[metabolism]] of drugs. It catalyzes the oxidation of substrates by adding an oxygen atom, which often results in increased water solubility and facilitates excretion from the body. The enzyme is known for its ability to metabolize a wide variety of structurally diverse compounds, making it a key player in drug metabolism.


Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 [[enzyme substrate|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#Pharmacology|efficacy]] while if the drug is metabolized too slowly, toxicity may result.<ref name="pmid22185816"/>  So, the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.<ref name="pmid22515611">{{cite journal | vauthors = Walko CM, McLeod H | title = Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment | journal = Pharmacogenomics | volume = 13 | issue = 6 | pages = 691–7 | date = April 2012 | pmid = 22515611 | doi = 10.2217/pgs.12.27 }}</ref>
==Genetic Variability==
The CYP2D6 gene is highly polymorphic, meaning there are many different genetic variants that can affect enzyme activity. These genetic differences can lead to varying levels of enzyme activity, classifying individuals into different metabolizer phenotypes:


Other drugs may function as [[enzyme inhibitor|inhibitor]]s of CYP2D6 activity or [[inducer]]s 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 interaction|drug-drug interaction]].<ref name="pmid22185816">{{cite journal | vauthors = Teh LK, Bertilsson L | title = Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance | journal = Drug Metabolism and Pharmacokinetics | volume = 27 | issue = 1 | pages = 55–67 | year = 2012 | pmid = 22185816 | doi = 10.2133/dmpk.DMPK-11-RV-121 }}</ref>
* '''Poor Metabolizers (PM)''': Individuals with little or no CYP2D6 function.
* '''Intermediate Metabolizers (IM)''': Individuals with reduced CYP2D6 function.
* '''Extensive Metabolizers (EM)''': Individuals with normal CYP2D6 function.
* '''Ultrarapid Metabolizers (UM)''': Individuals with multiple copies of the CYP2D6 gene, leading to increased enzyme activity.


== Gene ==
These phenotypes can significantly influence the pharmacokinetics and pharmacodynamics of drugs metabolized by CYP2D6, affecting both efficacy and risk of adverse effects.


The gene is located near two cytochrome P450 [[pseudogene]]s on chromosome 22q13.1. [[alternative splicing|Alternatively spliced]] transcript variants encoding different [[isoform]]s have been found for this gene.<ref>{{cite web | title = Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565 }}</ref>
==Clinical Significance==
CYP2D6 is involved in the metabolism of several important drugs, including:


== Genotype/phenotype variability ==
* [[Codeine]]: Metabolized to morphine, which is responsible for its analgesic effects.
* [[Tamoxifen]]: Metabolized to its active form, endoxifen, used in the treatment of [[breast cancer]].
* [[Metoprolol]]: A beta-blocker used in the treatment of [[hypertension]] and [[heart failure]].


CYP2D6 shows the largest [[phenotype|phenotypical]] variability among the CYPs, largely due to [[genetics|genetic]] [[polymorphism (biology)|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.<ref name="PMID24413808" />
The variability in CYP2D6 activity can lead to differences in drug response and toxicity. For example, poor metabolizers may experience reduced therapeutic effects or increased side effects, while ultrarapid metabolizers may require higher doses to achieve therapeutic effects.
The CYP2D6 function in any particular subject may be described as one of the following:<ref name="pmid11851634">{{cite journal | vauthors = Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A | title = Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs | journal = British Journal of Clinical Pharmacology | volume = 53 | issue = 2 | pages = 111–22 | date = February 2002 | pmid = 11851634 | pmc = 1874287 | doi = 10.1046/j.0306-5251.2001.01548.x }}</ref>
* 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, so greater-than-normal CYP2D6 function occurs


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).<ref name="pmid19102711">{{cite journal | vauthors = Llerena A, Dorado P, Peñas-Lledó EM | title = Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity | journal = Pharmacogenomics | volume = 10 | issue = 1 | pages = 17–28 | date = January 2009 | pmid = 19102711 | doi = 10.2217/14622416.10.1.17 }}</ref>
==Drug Interactions==
CYP2D6 is subject to inhibition and induction by various drugs, which can lead to significant drug-drug interactions. Inhibitors of CYP2D6, such as [[fluoxetine]] and [[quinidine]], can decrease the metabolism of CYP2D6 substrates, potentially leading to increased plasma concentrations and adverse effects. Conversely, inducers can increase the metabolism of substrates, reducing their efficacy.


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.<ref name="pmid17708140">{{cite journal | vauthors = Lynch T, Price A | title = The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects | journal = American Family Physician | volume = 76 | issue = 3 | pages = 391–6 | date = August 2007 | pmid = 17708140 }}</ref>
==Related Pages==
* [[Cytochrome P450]]
* [[Drug metabolism]]
* [[Pharmacogenomics]]
* [[Enzyme inhibition]]


== Genetic basis of variability ==
[[Category:Cytochrome P450]]
 
[[Category:Drug metabolism]]
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.<ref name="PMID24413808">{{cite journal | vauthors = Dinama O, Warren AM, Kulkarni J | title = The role of pharmacogenomic testing in psychiatry: Real world examples | journal = The Australian and New Zealand Journal of Psychiatry | volume = 48 | issue = 8 | pages = 778 | date = August 2014 | pmid = 24413808 | doi = 10.1177/0004867413520050 }}</ref>
[[Category:Pharmacogenetics]]
 
{| width="50%" border="0" cellpadding="2" cellspacing="2"
| bgcolor="#cccccc" colspan="2" | '''''CYP2D6'' enzyme activity for selected alles'''<ref name="Droll_1998"/><ref>{{cite web|url=http://www.cypalleles.ki.se/cyp2d6.htm| title= CYP2D6 allele nomenclature|accessdate=5 February 2016}}</ref>
|-
| width="50%" bgcolor="#cccccc" | Allele
| width="50%" bgcolor="#cccccc" | CYP2D6 activity
|-
| bgcolor="#efefef" | ''CYP2D6*1''
| bgcolor="#dfefff" | normal
|-
| bgcolor="#efefef" | ''CYP2D6*2''
| bgcolor="#dfefff" | normal
|-
| bgcolor="#efefef" | ''CYP2D6*3''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*4''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*5''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*6''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*7''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*8''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*9''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*10''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*11''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*12''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*13''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*14''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*15''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*17''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*19''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*20''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*21''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*29''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*31''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*38''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*40''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*41''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*42''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*68''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*92''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*100''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6*101''
| bgcolor="#dfefff" | none
|-
| bgcolor="#efefef" | ''CYP2D6 duplication''
| bgcolor="#dfefff" | increased
|}
 
== Ethnic factors in variability ==
 
Race is a factor in the occurrence of CYP2D6 variability. The lack of the liver cytochrome CYP2D6 enzyme occurs approximately in 7–10% in [[White people|white]] populations, and is lower in most other ethnic groups such as [[Asian people|Asians]] and [[African-Americans]] at 2% each.<ref>{{Cite book|title=Pharmacology and the Nursing Process|last=Lilley, Harrington, Snyder, Swart|first=Linda Lane, Scott, Julie, Beth|publisher=Mosby Elsevier|year=2007|isbn=9780779699711|location=Toronto|pages=25}}</ref> The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among [[Middle East]]ern and [[North Africa]]n populations.<ref name="pmid9241658">{{cite journal | vauthors = McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M | title = Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians | journal = Pharmacogenetics | volume = 7 | issue = 3 | pages = 187–91 | date = June 1997 | pmid = 9241658 | doi = 10.1097/00008571-199706000-00003 }}</ref>
 
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.<ref name="pmid11972444">{{cite journal | vauthors = Bradford LD | title = CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants | journal = Pharmacogenomics | volume = 3 | issue = 2 | pages = 229–43 | date = March 2002 | pmid = 11972444 | doi = 10.1517/14622416.3.2.229 }}</ref>
 
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,<ref name="Droll_1998">{{cite journal | vauthors = Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF | title = Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians | journal = Pharmacogenetics | volume = 8 | issue = 4 | pages = 325–33 | date = August 1998 | pmid = 9731719 | doi = 10.1097/00008571-199808000-00006 }}</ref> while approximately 50% of Asians possess the decreased functioning ''CYP2D6*10'' allele.<ref name="Droll_1998" />
 
== Ligands ==
Following is a table of selected [[enzyme substrate|substrates]], [[enzyme induction and inhibition|inducers]] and [[enzyme induction and inhibition|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 (pharmacology)|potency]], such as:
*'''Strong inhibitor''' being one that causes at least a 5-fold increase in the plasma [[area under the curve (pharmacokinetics)|AUC values]] of sensitive substrates metabolized through CYP2D6, or more than 80% decrease in [[clearance (medicine)|clearance]] thereof.<ref name=Flockhart/>
*'''Moderate inhibitor''' being one that causes at least a 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP2D6, or 50-80% decrease in clearance thereof.<ref name=Flockhart/>
*'''Weak inhibitor''' being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP2D6, or 20-50% decrease in clearance thereof.<ref name=Flockhart/>
 
{| class="wikitable" width=100%
|+'''Selected inducers, inhibitors and substrates of CYP2D6'''
|-
! Substrates<br />↑ <small>= [[bioactivation]] by CYP2D6</small> !! Inhibitors !! Inducers
|- style="vertical-align: top;"
|<!--substrates-->
* All<ref name=FASS/> [[tricyclic antidepressants]], e.g.
** [[imipramine]]<ref name=Flockhart/>
** [[amitriptyline]]<ref name=Flockhart/>
** etc.
* Most<ref name=FASS/> [[SSRI]]s (antidepressant), e.g.
** [[fluoxetine]]<ref name=Flockhart/>
** [[paroxetine]]<ref name=Flockhart/>
** [[fluvoxamine]]<ref name=Flockhart/>
* [[venlafaxine]]<ref name=Flockhart/><ref name=FASS/> ([[serotonin-norepinephrine reuptake inhibitor|SNRI]] antidepressant)
* [[duloxetine]]<ref name=Flockhart/> ([[serotonin-norepinephrine reuptake inhibitor|SNRI]], moderate sensitive substrates of CYP2D6<ref name=Flockhart/>)
* [[mianserin]]<ref name=FASS/> ([[tetracyclic antidepressant]])
* [[mirtazapine]]<ref name=FASS/> ([[antidepressant]])
* [[opioids]]
** [[codeine]]<ref name=Flockhart/><ref name=FASS/> [[bioactivation|&uarr;]][into [[morphine]]]<ref name=Leeder>{{cite journal | vauthors = Leeder JS | title = Pharmacogenetics and pharmacogenomics | journal = Pediatric Clinics of North America | volume = 48 | issue = 3 | pages = 765–81 | date = June 2001 | pmid = 11411304 | doi = 10.1016/S0031-3955(05)70338-2 }}</ref>
** [[tramadol]]<ref name=Flockhart/><ref name=FASS/> [[bioactivation|&uarr;]][into [[O-desmethyltramadol]]]<ref name=Leeder/>
** [[O-desmethyltramadol]] [[bioactivation|&uarr;]][into N,O-didesmethyltramadol]
** [[N-desmethyltramadol]] [inactive] [[bioactivation|&uarr;]][into N,O-didesmethyltramadol]
** [[oxycodone]]<ref name=Flockhart/>
** [[hydrocodone]] [[bioactivation|&uarr;]][into [[hydromorphone]]]<ref>{{cite web |url= http://www.drugbank.ca/drugs/DB00956 |title= Hydrocodone |publisher= Drugbank |accessdate=14 June 2011}}</ref>
** [[tapentadol]]
* [[antipsychotics]], e.g.
** [[haloperidol]]<ref name=Flockhart/><ref name=FASS/>
** [[risperidone]]<ref name=Flockhart/><ref name=FASS/>
** [[perphenazine]]<ref name=Flockhart/><ref name=FASS/>
** [[thioridazine]]<ref name=Flockhart/><ref name=FASS/>
** [[zuclopenthixol]]<ref name=Flockhart/><ref name=FASS/>
** [[iloperidone]]<ref name=Flockhart/><ref name=FASS/>
** [[aripiprazole]]<ref name=Flockhart/><ref name=FASS/>
** [[chlorpromazine]]<ref name=Flockhart/><ref name=FASS/>
** [[levomepromazine]]<ref name=FASS/>
** [[remoxipride]]<ref name=FASS/>
* [[minaprine]]<ref name=Flockhart/> ([[reversible inhibitor of MAO-A|RIMA]] antidepressant)
* [[tamoxifen]]<ref name=Flockhart/><ref name=FASS/> [[bioactivation|&uarr;]][into [[hydroxytamoxifen]]]<ref name="pmid19629072">{{cite journal | vauthors = Hoskins JM, Carey LA, McLeod HL | title = CYP2D6 and tamoxifen: DNA matters in breast cancer | journal = Nature Reviews. Cancer | volume = 9 | issue = 8 | pages = 576–86 | date = August 2009 | pmid = 19629072 | doi = 10.1038/nrc2683 }}</ref> ([[selective estrogen receptor modulator|SERM]])
* [[beta-blockers]]
** [[metoprolol]]<ref name=Flockhart/><ref name=FASS/>
** [[timolol]]<ref name=Flockhart/><ref name=FASS/>
** [[alprenolol]]<ref name=Flockhart/><ref name=FASS/>
** [[carvedilol]]<ref name=Flockhart/>
** [[bufuralol]]<ref name=Flockhart/>
** [[nebivolol]]<ref name=Flockhart/>
** [[propranolol]]<ref name=Flockhart/>
* [[debrisoquine]]<ref name=Flockhart/> ([[antihypertensive]])
* Class I [[antiarrhythmics]]
** [[flecainide]]<ref name=Flockhart/><ref name=FASS/>
** [[propafenone]]<ref name=Flockhart/><ref name=FASS/>
** [[encainide]]<ref name=Flockhart/><ref name=FASS/>
** [[mexiletine]]<ref name=Flockhart/><ref name=FASS/>
** [[lidocaine]] <ref name=Flockhart/>
** [[sparteine]]<ref name=Flockhart/>
* [[ondansetron]]<ref name=Flockhart/><ref name=FASS/> ([[antiemetic]])
* [[donepezil]]<ref name=Flockhart/><ref name=FASS/> ([[acetylcholinesterase inhibitor]])
* [[phenformin]]<ref name=Flockhart/><ref name=FASS/> ([[antidiabetic]])
* [[tropisetron]]<ref name=FASS/> ([[5-HT3 receptor antagonist]])
* [[stimulants]]
** [[amphetamine]]<ref name=Flockhart/>
** [[methoxyamphetamine]]<ref name=Flockhart/>
** [[dextromethamphetamine]]<ref name=Flockhart/>
*  [[Norepinephrine reuptake inhibitor|NRI]]
** [[atomoxetine]] (Sensitive substrate of CYP2D6) <ref name=Flockhart/>
* [[chlorphenamine]]<ref name=Flockhart/> ([[antihistamine]])
* [[dexfenfluramine]]<ref name=Flockhart/> ([[serotonin]]ergic [[anorectic]])
* [[dextromethorphan]]<ref name=Flockhart/> [[bioactivation|&uarr;]][into [[dextrorphan]]] ([[antitussive]])
* [[metoclopramide]]<ref name=Flockhart/> ([[dopamine antagonist]])
* [[perhexiline]]<ref name=Flockhart/> ([[antianginal agent]])
* [[phenacetin]]<ref name=Flockhart/> ([[analgesic]])
* [[promethazine]]<ref name=Flockhart/> ([[antihistamine]] [[antiemetic]])
* [[m-tyramine|''m''-tyramine]]<ref name="CYP2D6 tyramine-dopamine metabolism" />
* [[p-tyramine|''p''-tyramine]]<ref name="CYP2D6 tyramine-dopamine metabolism" />
* [[Calcium channel blocker]]
** [[diltiazem]] (minor/moderate sensitive substrate) <ref name="DailyMed 2017">{{cite web | title=DILTIAZEM HCL CD- diltiazem hydrochloride capsule, coated, extended release | website=DailyMed | date=2017-02-01 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e39be50-ea17-4077-a2dc-668267049f6a | access-date=2019-01-31}}</ref>
** [[nifedipine]] (minor/moderate sensitive substrate)<ref name="DailyMed 2012">{{cite web | title=NIFEDIPINE EXTENDED RELEASE- nifedipine tablet, extended release | website=DailyMed | date=2012-11-29 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4617417a-08df-4417-a944-dfc30de183db | access-date=2019-02-01}}</ref>
||
 
'''Strong'''<!--inhibitors-->
* Certain [[Selective serotonin reuptake inhibitor|SSRI]]s
** [[fluoxetine]]<ref name=Flockhart/><ref name=FASS>[[FASS (drug formulary)]]: [http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish environmental classification of pharmaceuticals] Facts for prescribers (Fakta för förskrivare), retrieved July 2011</ref>
** [[paroxetine]]<ref name=Flockhart/><ref name=FASS/>
* [[bupropion]]<ref name=Flockhart/><ref name="pmid15876900">{{cite journal | vauthors = Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE | title = Inhibition of CYP2D6 activity by bupropion | journal = Journal of Clinical Psychopharmacology | volume = 25 | issue = 3 | pages = 226–9 | date = June 2005 | pmid = 15876900 | doi = 10.1097/01.jcp.0000162805.46453.e3 }}</ref> (non-SSRI antidepressant)
* [[quinidine]]<ref name=Flockhart/><ref name=FASS/> ([[class I antiarrhythmic agent]])
* [[quinine]]<ref>{{cite journal | vauthors = Fasinu PS, Tekwani BL, Avula B, Chaurasiya ND, Nanayakkara NP, Wang YH, Khan IA, Walker LA | title = Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine | journal = Malaria Journal | volume = 15 | pages = 466 | date = September 2016 | pmid = 27618912 | doi = 10.1186/s12936-016-1509-x | pmc=5020452}}</ref>
* [[cinacalcet]]<ref name=Flockhart/> (calcimimetic)
* [[ritonavir]]<ref name=FASS/> ([[antiretroviral]])
* [[cannabidiol]]<ref>{{Cite web|url=https://doh.dc.gov/sites/default/files/dc/sites/doh/publication/attachments/Medical%20Cannabis%20Adverse%20Effects%20and%20Drug%20Interactions_0.pdf|title=Medical Cannabis  Adverse Effects & Drug Interactions|last=|first=|date=|website=|url-status=live|archive-url=|archive-date=|access-date=}}</ref>
 
'''Moderate'''<!--inhibitors-->
* [[sertraline]]<ref name=Flockhart/> ([[Selective serotonin reuptake inhibitor|SSRI]])
* [[duloxetine]]<ref name=Flockhart/> ([[serotonin-norepinephrine reuptake inhibitor|SNRI]])
* [[terbinafine]]<ref name=Flockhart/> ([[Antifungal medication|antifungal]])
 
'''Weak'''<!--inhibitors-->
* [[amiodarone]]<ref name=Flockhart>{{cite web |author=Flockhart DA |title=Drug Interactions: Cytochrome P<sub>450</sub> Drug Interaction Table |publisher=[[Indiana University School of Medicine]] |year=2007 |url=http://medicine.iupui.edu/flockhart/table.htm}} Retrieved in July 2011</ref> ([[antiarrhythmic]])
* [[buprenorphine]]<ref name="pmid12756210">{{cite journal | vauthors = Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM | title = Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro | journal = Drug Metabolism and Disposition | volume = 31 | issue = 6 | pages = 768–72 | date = June 2003 | pmid = 12756210 | doi = 10.1124/dmd.31.6.768 }}</ref> (in opioid addiction)
* [[cimetidine]]<ref name=Flockhart/> ([[H2-receptor antagonist]])
* [[citalopram]]<ref name=Flockhart/><ref name = "drugs.com">{{cite web | url = https://www.drugs.com/pro/citalopram-oral-solution.html|title = Citalopram Oral Solution | work = Drugs.com }}</ref> ([[Selective serotonin reuptake inhibitor|SSRI]])
* [[escitalopram]]<ref name=Flockhart/><ref name = "drugs.com" /><ref name="UpToDate Escitalopram">{{cite web | title=Escitalopram-drug-information | website=UpToDate | url=https://www.uptodate.com/contents/escitalopram-drug-information | access-date=2019-05-22}}</ref> ([[Selective serotonin reuptake inhibitor|SSRI]])
* [[methylphenidate]] <ref>{{cite journal | url = http://www.gjpsy.uni-goettingen.de/gjp-article-nevels.pdf | title = Methylphenidate and Its Under-recognized, Under- explained, and Serious Drug Interactions: A Review of the Literature with Heightened Concerns | journal = German Journal of Psychiatry | date = July 2013 | pages = 29–42 | vauthors = Nevels RM, Weiss NH, Killebrew AE, Gontkovsky ST }}</ref>
* [[diltiazem]] <ref name="DailyMed 2017"/>
* [[felodipine]] <ref name="Bailey Bend Arnold Tran 1996 pp. 25–33">{{cite journal | last=Bailey | first=David G. | last2=Bend | first2=John R. | last3=Arnold | first3=J. Malcolm O. | last4=Tran | first4=Lan T. | last5=Spence | first5=J. David | title=Erythromycin-felodipine interaction: Magnitude, mechanism, and comparison with grapefruit juice* | journal=Clinical Pharmacology and Therapeutics | volume=60 | issue=1 | year=1996 | issn=0009-9236 | pmid=8689808 | doi=10.1016/s0009-9236(96)90163-0 | pages=25–33}}</ref><ref name="Lown Bailey Fontana Janardan pp. 2545–2553">{{cite journal | last=Lown | first=K S | last2=Bailey | first2=D G | last3=Fontana | first3=R J | last4=Janardan | first4=S K | last5=Adair | first5=C H | last6=Fortlage | first6=L A | last7=Brown | first7=M B | last8=Guo | first8=W | last9=Watkins | first9=P B | title=Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. | journal=The Journal of Clinical Investigation | volume=99 | issue=10 | date=1997-05-15 | issn=0021-9738 | pmid=9153299 | pmc=508096 | doi=10.1172/jci119439 | pages=2545–2553}}</ref><ref name="Guengerich Brian Iwasaki Sari 1991 pp. 1838–44">{{cite journal | last=Guengerich | first=FP | last2=Brian | first2=WR | last3=Iwasaki | first3=M | last4=Sari | first4=MA | last5=Bäärnhielm | first5=C | last6=Berntsson | first6=P | title=Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4. | journal=Journal of Medicinal Chemistry | volume=34 | issue=6 | year=1991 | issn=0022-2623 | pmid=2061924 | pages=1838–44| doi=10.1021/jm00110a012 }}</ref>
*[[mirtazapine]]<ref>{{Cite journal|last=Owen|first=J. Randall|last2=Nemeroff|first2=Charles|date=1998-05-30|title=New antidepressants and the cytochrome P450 system: Focus on venlafaxine, nefazodone, and mirtazapine|url=https://researchers.dellmed.utexas.edu/en/publications/new-antidepressants-and-the-cytochrome-psub450sub-system-focus-on|journal=Depression and Anxiety|volume=7|issue=SUPPL. 1|pages=24–32|doi=10.1002/(SICI)1520-6394(1998)7:1+3.0.CO;2-F|issn=1091-4269|pmid=9597349}}</ref>
 
'''<!--inhibitors of-->Unspecified potency'''
* [[antipsychotic]]s
** [[haloperidol]]<ref name=fass-codeine>[[FASS (drug formulary)|FASS]], [http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=19731109000032&DocTypeID=6 The Swedish official drug catalog > Kodein Recip] Last reviewed 2008-04-08</ref><ref name=Flockhart/>
** [[perphenazine]]<ref name=Flockhart/><ref name=fass-codeine/>
** [[thioridazine]]<ref name=fass-codeine/>
** [[zuclopenthixol]]<ref name=fass-codeine/>
** [[chlorpromazine]]<ref name=Flockhart/>
* [[hyperforin]] ([[St. Johns Wort]])<ref>{{cite journal |doi=10.1080/13880200490512034 |title=''In Vitro'' Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein |journal=Pharmaceutical Biology |volume=42 |issue=2 |pages=159–69 |year=2008 |last1=Foster |first1=B.C |last2=Sockovie |first2=E.R |last3=Vandenhoek |first3=S |last4=Bellefeuille |first4=N |last5=Drouin |first5=C.E |last6=Krantis |first6=A |last7=Budzinski |first7=J.W |last8=Livesey |first8=J |last9=Arnason |first9=J.T }}</ref>
* [[antihistamine]]s ([[H1-receptor antagonists]])
** [[promethazine]]<ref name="pmid11936702">{{cite journal | vauthors = He N, Zhang WQ, Shockley D, Edeki T | title = Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes | journal = European Journal of Clinical Pharmacology | volume = 57 | issue = 12 | pages = 847–51 | date = February 2002 | pmid = 11936702 | doi = 10.1007/s00228-001-0399-0 }}</ref> ([[sedative|antipsychotic]])
** [[chlorphenamine]]<ref name=Flockhart/>
** [[diphenhydramine]]<ref name=Flockhart/>
** [[hydroxyzine]]<ref name=Flockhart/>
** [[tripelennamine]]<ref name=Flockhart/>
* [[clemastine]]<ref name=Flockhart/> ([[antihistamine]] and [[anticholinergic]])
* [[celecoxib]]<ref name=Flockhart/> ([[NSAID]])
* [[clomipramine]]<ref name=Flockhart/> ([[tricyclic antidepressant]])
* [[cocaine]]<ref name=Flockhart/> ([[stimulant]])
* [[doxorubicin]]<ref name=Flockhart/> ([[chemotherapeutic]])
* [[metoclopramide]]<ref name=Flockhart/> ([[antiemetic]], [[prokinetic]])
* [[methadone]]<ref name=Flockhart/> ([[analgesic]] and [[anti-addictive]])
* [[moclobemide]]<ref name=Flockhart/> ([[antidepressant]])
* [[niacin]]<ref name = "Gaudineau_2004">{{cite journal | vauthors = Gaudineau C, Auclair K | title = Inhibition of human P450 enzymes by nicotinic acid and nicotinamide | journal = Biochemical and Biophysical Research Communications | volume = 317 | issue = 3 | pages = 950–6 | date = May 2004 | pmid = 15081432 | doi = 10.1016/j.bbrc.2004.03.137 }}</ref> ([[vitamin]])
* [[nicotinamide]]<ref name = "Gaudineau_2004" /> ([[vitamin]])
* [[doxepin]]<ref name=Flockhart/> ([[tricyclic antidepressant]], [[anxiolytic]])
* [[halofantrine]]<ref name=Flockhart/> (in [[malaria]])
* [[levomepromazine]]<ref name=Flockhart/> ([[antipsychotic]])
* [[mibefradil]]<ref name=Flockhart/> ([[calcium channel blocker]])
* [[midodrine]]<ref name=Flockhart/> ([[Alpha-1 adrenergic agonist|α<sub>1</sub> agonist]])
* [[ticlopidine]]<ref name=Flockhart/> ([[antiplatelet drug|antiplatelet]])
||
 
'''Strong'''<!--inducers-->
* [[glutethimide]]<!-- <ref name=Dave/> --> ([[hypnotic|hypnotic sedative]])
'''<!--inducers of-->Unspecified potency'''
* [[dexamethasone]]<ref name=Flockhart/> ([[glucocorticoid]])
* [[rifampicin]]<ref name=Flockhart/> ([[bactericidal]])
* [[haloperidol]]<ref>{{cite journal | vauthors = Kudo S, Ishizaki T | title = Pharmacokinetics of haloperidol: an update | journal = Clinical Pharmacokinetics | volume = 37 | issue = 6 | pages = 435–56 | date = December 1999 | pmid = 10628896 | doi = 10.2165/00003088-199937060-00001 }}</ref> ([[typical antipsychotic]])
|-
|}
 
===Dopamine biosynthesis===
{{Catecholamine and trace amine biosynthesis|caption=In humans, [[catecholamine]]s and phenethylaminergic [[trace amine]]s 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.<ref name="CYP2D6 tyramine-dopamine metabolism" /> Similarly, CYP2D6 also metabolizes [[m-tyramine|''m''-tyramine]] into dopamine.<ref name="CYP2D6 tyramine-dopamine metabolism" />}}
 
== References ==
{{reflist|colwidth=35em}}
 
== Further reading ==
{{refbegin|colwidth=35em}}
* {{cite journal | vauthors = Smith G, Stubbins MJ, Harries LW, Wolf CR | title = Molecular genetics of the human cytochrome P450 monooxygenase superfamily | journal = Xenobiotica | volume = 28 | issue = 12 | pages = 1129–65 | date = December 1998 | pmid = 9890157 | doi = 10.1080/004982598238868 }}
* {{cite journal | vauthors = Wolf CR, Smith G | title = Cytochrome P450 CYP2D6 | journal = IARC Scientific Publications | issue = 148 | pages = 209–29 | year = 1999 | pmid = 10493260 }}
* {{cite journal | vauthors = Ding X, Kaminsky LS | title = Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts | journal = Annual Review of Pharmacology and Toxicology | volume = 43 | pages = 149–73 | year = 2003 | pmid = 12171978 | doi = 10.1146/annurev.pharmtox.43.100901.140251 }}
* {{cite journal | vauthors = Lilienfeld S | title = Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease | journal = CNS Drug Reviews | volume = 8 | issue = 2 | pages = 159–76 | year = 2006 | pmid = 12177686 | doi = 10.1111/j.1527-3458.2002.tb00221.x | pmc = 6741688 }}
* {{cite journal | vauthors = Yu AM, Idle JR, Gonzalez FJ | title = Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates | journal = Drug Metabolism Reviews | volume = 36 | issue = 2 | pages = 243–77 | date = May 2004 | pmid = 15237854 | doi = 10.1081/DMR-120034000 | url = https://zenodo.org/record/1236072 }}
* {{cite journal | vauthors = Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Shah M, Ingle S, Greenberg D, Earl HM, Dunning AM, Pharoah PD, Caldas C | title = CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen | journal = Breast Cancer Research | volume = 12 | issue = 4 | pages = R64 | year = 2010 | pmid = 20731819 | pmc = 2949659 | doi = 10.1186/bcr2629 }}
* {{cite journal | vauthors = Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Earl HM, Dunning AM, Pharoah PD, Caldas C | title = CYP2D6 gene variants and their association with breast cancer susceptibility | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 20 | issue = 6 | pages = 1255–8 | date = June 2011 | pmid = 21527579 | doi = 10.1158/1055-9965.EPI-11-0321 }}
{{refend}}
 
== External links ==
* [http://medicine.iupui.edu/flockhart/2D6.htm#2D6sub Flockhart Lab Cyp2D6 Substrates Page] at [[Indiana University-Purdue University Indianapolis|IUPUI]]
* [https://web.archive.org/web/20081207081045/http://www.pharmgkb.org/search/annotatedGene/cyp2d6/index.jsp PharmGKB: Annotated PGx Gene Information for CYP2D6]
* {{UCSC gene info|CYP2D6}}
 
{{PDB Gallery|geneid=1565}}
{{Cytochrome P450}}
{{Dioxygenases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}
 
[[Category:Cytochrome P450|2]]
[[Category:EC 1.14.14]]
[[Category:Amphetamine]]
{{dictionary-stub1}}
{{No image}}

Latest revision as of 19:17, 22 March 2025

Human cytochrome P450 enzyme



Overview[edit]

CYP2D6 (Cytochrome P450 2D6) is an important enzyme in the cytochrome P450 superfamily, which is involved in the metabolism of many drugs and xenobiotics in the body. It is encoded by the CYP2D6 gene located on chromosome 22q13.1. This enzyme is responsible for the oxidative metabolism of approximately 25% of all clinically used medications, including antidepressants, antipsychotics, beta-blockers, and opioids.

Function[edit]

CYP2D6 is primarily expressed in the liver, where it plays a crucial role in the metabolism of drugs. It catalyzes the oxidation of substrates by adding an oxygen atom, which often results in increased water solubility and facilitates excretion from the body. The enzyme is known for its ability to metabolize a wide variety of structurally diverse compounds, making it a key player in drug metabolism.

Genetic Variability[edit]

The CYP2D6 gene is highly polymorphic, meaning there are many different genetic variants that can affect enzyme activity. These genetic differences can lead to varying levels of enzyme activity, classifying individuals into different metabolizer phenotypes:

  • Poor Metabolizers (PM): Individuals with little or no CYP2D6 function.
  • Intermediate Metabolizers (IM): Individuals with reduced CYP2D6 function.
  • Extensive Metabolizers (EM): Individuals with normal CYP2D6 function.
  • Ultrarapid Metabolizers (UM): Individuals with multiple copies of the CYP2D6 gene, leading to increased enzyme activity.

These phenotypes can significantly influence the pharmacokinetics and pharmacodynamics of drugs metabolized by CYP2D6, affecting both efficacy and risk of adverse effects.

Clinical Significance[edit]

CYP2D6 is involved in the metabolism of several important drugs, including:

The variability in CYP2D6 activity can lead to differences in drug response and toxicity. For example, poor metabolizers may experience reduced therapeutic effects or increased side effects, while ultrarapid metabolizers may require higher doses to achieve therapeutic effects.

Drug Interactions[edit]

CYP2D6 is subject to inhibition and induction by various drugs, which can lead to significant drug-drug interactions. Inhibitors of CYP2D6, such as fluoxetine and quinidine, can decrease the metabolism of CYP2D6 substrates, potentially leading to increased plasma concentrations and adverse effects. Conversely, inducers can increase the metabolism of substrates, reducing their efficacy.

Related Pages[edit]

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