CYP2D6
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2008-07-08T00:52:09Z
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{{PBB|geneid=1565}}
'''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 [[xenobiotic]]s in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the [[Cytochrome P450|CYP]]s, there is considerable variability in its expression in the liver. 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 = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565| accessdate = }}</ref>
==Genotype/phenotype variability==
CYP2D6 shows the largest [[phenotype|phenotypical]] variability amongst the CYPs, largely due to [[genetics|genetic]] [[polymorphism (biology)|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 somewhat 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 CYP450 Test|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.
{| width="50%" border="0" align="center" cellpadding="2" cellspacing="2"
| colspan="2" bgcolor="#CCCCCC" | '''''CYP2D6'' allele and enzyme activity''' (after Droll ''et al''., 1998)
|-
| width="50%" bgcolor="#CCCCCC" | Allele
| width="50%" bgcolor="#CCCCCC" | CYP2D6 activity
|-
| bgcolor="#efefef" | ''CYP2D6*1''
| 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*9''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*10''
| bgcolor="#dfefff" | decreased
|-
| bgcolor="#efefef" | ''CYP2D6*17''
| bgcolor="#dfefff" | 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 people|white]] populations, but is lower in most other ethnic groups such as [[Asian people|Asians]] (2%)<ref>Australian Medicines Handbook (AMH) ''2004. ISBN 0-9578521-4-2''</ref>. In [[Black people|blacks]], the frequency of poor metabolizers is greater than for whites<ref>{{cite journal |author=Gaedigk A, Bradford LD, Marcucci KA, Leeder JS |title=Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans |journal=Clin. Pharmacol. Ther. |volume=72 |issue=1 |pages=76–89 |year=2002 |pmid=12152006 |doi=10.1067/mcp.2002.125783}}</ref>. The occurrence of CYP2D6 ultrarapid metabolisers appears to be greater amongst [[Middle East]]ern and [[North Africa]]n populations<ref>{{cite journal |author=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 |year=1997 |pmid=9241658 |doi=10.1097/00008571-199706000-00003}}</ref>.
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<ref name="pmid9731719">{{cite journal |author=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 |year=1998 |pmid=9731719 |doi=10.1097/00008571-199808000-00006}}</ref> while approximately 50% of Asians possess the ''CYP2D6*10'' allele<ref name="pmid9731719" />, which should produce decreased CYP2D6 function; however this still appears to be within the normal range and are still grouped as extensive metabolisers.
==CYP2D6 [[Ligand (biochemistry)|Ligands]]==
{| class="wikitable" width=100%
|+'''Selected inducers, inhibitors and substrates of CYP2D6<ref>Where classes of agents are listed, there may be exceptions within the class</ref>'''
|-
! Substrates !! Inhibitors !! Inducers
|- style="vertical-align: top;"
| '''Often mentioned''': <ref name=importance> Mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems</ref>
* [[beta-blockers]]
** [[metoprolol]]
** [[carvedilol]]
** [[timolol]]
* Class I [[antiarrhythmics]]
** [[flecainide]]
** [[lidocaine]]
** [[propafenone]]
** [[encainide]]
** [[mexiletine]]
* All [[tricyclic antidepressants]], e.g.
** [[imipramine]]
** [[amitriptyline]]
** etc.
* Most [[SSRI]]s, e.g.
** [[fluoxetine]]
** [[paroxetine]]
* [[opioids]]
** [[codeine]]
** [[tramadol]]
* [[debrisoquine]] ([[antihypertensive]])
* [[dextromethorphan]] ([[antitussive]])
* [[venlafaxine]] ([[serotonin-norepinephrine reuptake inhibitor|SNRI]])
* [[antipsychotics]], e.g.
** [[haloperidol]]
** [[risperidone]]
** [[perphenazine]]
** [[thioridazine]]
** [[zuclopenthixol]]
** [[remoxipride]]
** [[aripiprazole]]
* [[ondansetron]] ([[5-HT3 receptor antagonist]])
'''Other''':
* [[alprenolol]] ([[beta-blocker]])
* [[atenolol]] ([[beta-blocker]])
* [[mianserin]] ([[tetracyclic antidepressant]])
* [[phenformin]] ([[antidiabetic]])
* [[tropisetron]] ([[5-HT3 receptor antagonist]])
* [[amphetamine]] (in [[Attention-deficit hyperactivity disorder|ADHD]], [[narcolepsy]])
* [[chlorphenamine]] ([[antihistamine]])
* [[metoclopramide]] ([[dopamine antagonist]])
* [[tamoxifen]] ([[selective estrogen receptor modulator|SERM]])
* [[vinca alkaloid]]s ([[anti-mitotic]], anti-[[microtubule]])
** [[vincristine]]
|| '''Strong''': <ref name=FASS>[http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish environmental classification of pharmaceuticals] Facts for prescribers (Fakta för förskrivare)</ref>
* [[Selective serotonin reuptake inhibitor|SSRI]]s
** [[citalopram]]
** [[fluoxetine]]
** [[paroxetine]]
* [[terbinafine]] ([[antifungal]])
* [[quinidine]] ([[class I antiarrhythmic agent]])
'''unspecified''':
* [[amiodarone]] ([[antiarrhythmic]])
* [[antihistamine]] ([[H1-receptor antagonists]])
** [[chlorphenamine]]
** [[diphenhydramine]]
* [[antipsychotic]]
** [[chlorpromazine]]
** [[haloperidol]]
* [[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 agent|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:'''
* [[Piperidine]]s and derivatives ([[pharmacokinetics]] modifiers)
**[[glutethimide]] ([[piperidinedione]] derivative)
'''"Half"-Strong''':
* [[carbamazepine]]
'''Unspecified''':
* [[dexamethasone]] ([[glucocorticoid]])
* [[rifampicin]] ([[bactericidal]])
|-
|}
==References==
{{reflist}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=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 |year= 1999 |pmid= 9890157 |doi= }}
*{{cite journal | author=Wolf CR, Smith G |title=Cytochrome P450 CYP2D6 |journal=IARC Sci. Publ. |volume= |issue= 148 |pages= 209–29 |year= 1999 |pmid= 10493260 |doi= }}
*{{cite journal | author=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=Annu. Rev. Pharmacol. Toxicol. |volume=43 |issue= |pages= 149–73 |year= 2003 |pmid= 12171978 |doi= 10.1146/annurev.pharmtox.43.100901.140251 }}
*{{cite journal | author=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= 2002 |pmid= 12177686 |doi= }}
*{{cite journal | author=Yu AM, Idle JR, Gonzalez FJ |title=Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates |journal=Drug Metab. Rev. |volume=36 |issue= 2 |pages= 243–77 |year= 2004 |pmid= 15237854 |doi= 10.1081/DMR-120034000}}
}}
{{refend}}
==External links==
*[http://medicine.iupui.edu/flockhart/2D6.htm#2D6sub Flockhart Lab Cyp2D6 Substrates Page] at [[Indiana University-Purdue University Indianapolis|IUPUI]]
{{Oxygenases}}
{{Cytochrome P450}}
[[Category:Cytochrome P450]]
[[Category:EC 1.14.14]]
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