Editing CYP2D6 (section)

{{Short description|Human liver enzyme}}
{{Use dmy dates|date=December 2023}}
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{{Infobox_gene}}
'''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]].

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 | s2cid = 41857580 }}</ref>  CYP2D6 also activates some [[prodrug]]s. This enzyme also metabolizes several endogenous substances, such as [[N,N-Dimethyltryptamine]], [[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 = 211–218 | date = February 2014 | pmid = 24374199 | doi = 10.1016/j.ejphar.2013.12.025 }}</ref><ref name="Good et al 2023">
{{cite journal |
vauthors = Good M, Joel Z, Benway T, Routledge C, Timmermann C, Erritzoe D, Weaver R, Allen G, Hughes C, Topping H, Bowman A, James E |
title = Pharmacokinetics of N,N-dimethyltryptamine in Humans | journal = European Journal of Drug Metabolism and Pharmaco Kinetics | doi = 10.1007/s13318-023-00822-y | date = 2023-04-22 |
volume = 48 |
issue = 3 |
pages = 311–327 | pmid = 37086340 | pmc = 10122081}}</ref>

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 = 691–697 | date = April 2012 | pmid = 22515611 | doi = 10.2217/pgs.12.27 }}</ref> Individuals who exhibit an ultrarapid metabolizer phenotype, metabolize [[prodrug]]s, such as [[codeine]] or [[tramadol]], more rapidly, leading to higher than therapeutic levels.<ref name="pmid28520365">{{cite book|pmid=28520365 |date=2012 |title=Tramadol Therapy and CYP2D6 Genotype | vauthors = Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, Dean L, Kane M }}</ref><ref name="pmid28520350">{{cite book|pmid=28520350 |date=2012 |title=Codeine Therapy and CYP2D6 Genotype | vauthors = Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, Dean L, Kane M }}</ref> A case study of the death of an infant breastfed by an ultrarapid metabolizer mother taking codeine impacted postnatal pain relief clinical practices, but was later debunked.<ref name="pmid32378749">{{cite journal | vauthors = Zipursky J, Juurlink DN | title = The Implausibility of Neonatal Opioid Toxicity from Breastfeeding | journal = Clinical Pharmacology and Therapeutics | volume = 108 | issue = 5 | pages = 964–970 | date = November 2020 | pmid = 32378749 | doi = 10.1002/cpt.1882 | s2cid = 218535295 }}</ref> These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as after [[tonsillectomy]].<ref name="pmid22694279">{{cite journal | vauthors = Sadhasivam S, Myer CM | title = Preventing opioid-related deaths in children undergoing surgery | journal = Pain Medicine | volume = 13 | issue = 7 | pages = 982–3; author reply 984 | date = July 2012 | pmid = 22694279 | doi = 10.1111/j.1526-4637.2012.01419.x | doi-access = free }}</ref><ref name="pmid22492761">{{cite journal | vauthors = Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, Carleton B, Hayden MR, Madadi P, Koren G | title = More codeine fatalities after tonsillectomy in North American children | journal = Pediatrics | volume = 129 | issue = 5 | pages = e1343–e1347 | date = May 2012 | pmid = 22492761 | doi = 10.1542/peds.2011-2538 | url = https://publications.aap.org/pediatrics/article-pdf/129/5/e1343/896222/peds_2011-2538.pdf | access-date = 2 February 2024 | url-status = live | s2cid = 14167063 | archive-url = https://web.archive.org/web/20240202144200/https://publications.aap.org/pediatrics/article-pdf/129/5/e1343/896222/peds_2011-2538.pdf | archive-date = 2 February 2024 }}</ref><ref name="pmid24122716">{{cite journal | vauthors = Prows CA, Zhang X, Huth MM, Zhang K, Saldaña SN, Daraiseh NM, Esslinger HR, Freeman E, Greinwald JH, Martin LJ, Sadhasivam S | title = Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study | journal = The Laryngoscope | volume = 124 | issue = 5 | pages = 1242–1250 | date = May 2014 | pmid = 24122716 | doi = 10.1002/lary.24455 | s2cid = 5326129 }}</ref> 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>