Cytochrome P-450: Difference between revisions

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'''Cytochrome P-450''' is a "superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of [[steroid]]s, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism."<ref>{{MeSH}}</ref>
==Common abnormal alleles==
Isoforms CYP2C9, CYP2C19, and CYP2D6 account for 40% of metabolism by Cytochrome P-450.<ref name="pmid15625340">{{cite journal |author=Caraco Y |title=Genes and the response to drugs |journal=N. Engl. J. Med. |volume=351 |issue=27 |pages=2867–9 |year=2004 |month=December |pmid=15625340 |doi=10.1056/NEJMe048278 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=15625340 |issn=}}</ref>
===CYP1A2===
''CYP1A2'' is an [[isoenzyme]] of cytochrome P-450.<ref>{{OMIM|124060}}</ref> 12% of anglos are poor metabolizers of drugs that use the CYP1A2 [[isoenzyme]].<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |month=November |pmid=11710893 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11710893 |issn=}}</ref>
Slow metabolism may explain the association between [[caffeine]] and [[myocardial infarction]].<ref name="pmid16522833">{{cite journal |author=Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H |title=Coffee, CYP1A2 genotype, and risk of myocardial infarction |journal=JAMA |volume=295 |issue=10 |pages=1135–41 |year=2006 |month=March |pmid=16522833 |doi=10.1001/jama.295.10.1135 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=16522833 |issn=}}</ref>
===CYP2C9===
''CYP2C9'' is an [[isoenzyme]] of cytochrome P-450.<ref>{{OMIM|601130}}</ref>2-6% of anglos are poor metabolizers of drugs that use the CYP2C9[[isoenzyme]].<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |month=November |pmid=11710893 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11710893 |issn=}}</ref><ref name="pmid12571261">{{cite journal |author=Weinshilboum R |title=Inheritance and drug response |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=529–37 |year=2003 |month=February |pmid=12571261 |doi=10.1056/NEJMra020021 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571261&promo=ONFLNS19 |issn=}}</ref>
[[Genetic polymorphism|Polymorphisms]] of CYP2C9 explain 10% of variation in [[warfarin]] dosing<ref name="pmid15883587">{{cite journal |author=Wadelius M, Chen LY, Downes K, ''et al'' |title=Common VKORC1 and GGCX polymorphisms associated with warfarin dose |journal=Pharmacogenomics J. |volume=5 |issue=4 |pages=262-70 |year=2005 |pmid=15883587 |doi=10.1038/sj.tpj.6500313}}</ref>, mainly among Caucasian patients as these variants are rare in African American and most Asian populations.<ref name="pmid15714076">{{cite journal |author=Sanderson S, Emery J, Higgins J |title=CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis |journal=Genet. Med. |volume=7 |issue=2 |pages=97-104 |year=2005 |pmid=15714076 |doi=}}</ref> A [[meta-analysis]] of mainly Caucasian patients found<ref name="pmid15714076"/>:
* CYP2C9*2 allele:
** present in 12.2% of patients
** mean reduction was in warfarin dose was 0.85 mg (17% reduction)
** relative bleeding risk was 1.91
* CYP2C9*3 allele:
** present in 7.9% of patients
** mean reduction was in warfarin dose was 1.92 mg (37% reduction)
** relative bleeding risk was 1.77
===CYP2C19===
===CYP2C19===
''CYP2C19'' is an [[isoenzyme]] of cytochrome P-450.<ref>{{OMIM|124020}}</ref> 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 [[isoenzyme]].<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |month=November |pmid=11710893 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11710893 |issn=}}</ref><ref name="pmid12571261">{{cite journal |author=Weinshilboum R |title=Inheritance and drug response |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=529–37 |year=2003 |month=February |pmid=12571261 |doi=10.1056/NEJMra020021 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571261&promo=ONFLNS19 |issn=}}</ref> More recently, a study suggests that 30% of patients may have a reduced-function allele.<ref name="pmid19106084">{{cite journal |author=Mega JL, Close SL, Wiviott SD, ''et al'' |title=Cytochrome P-450 Polymorphisms and Response to Clopidogrel |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=December |pmid=19106084 |doi=10.1056/NEJMoa0809171 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106084&promo=ONFLNS19 |issn=}}</ref>
''CYP2C19'' is an [[isoenzyme]] of cytochrome P-450.<ref>{{OMIM|124020}}</ref> 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 [[isoenzyme]].<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |month=November |pmid=11710893 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11710893 |issn=}}</ref><ref name="pmid12571261">{{cite journal |author=Weinshilboum R |title=Inheritance and drug response |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=529–37 |year=2003 |month=February |pmid=12571261 |doi=10.1056/NEJMra020021 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571261&promo=ONFLNS19 |issn=}}</ref> More recently, a study suggests that 30% of patients may have a reduced-function allele.<ref name="pmid19106084">{{cite journal |author=Mega JL, Close SL, Wiviott SD, ''et al'' |title=Cytochrome P-450 Polymorphisms and Response to Clopidogrel |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=December |pmid=19106084 |doi=10.1056/NEJMoa0809171 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106084&promo=ONFLNS19 |issn=}}</ref>


CYP2C19 polymorphism affects response to [[clopidogrel]].  CYP2C19 loss-of-function alleles are associated with more cardiovascular events.<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref> Concomitant [[proton pump inhibitor]]s, which are also metabolized by CYP2C19, may<ref name="pmid19258584">{{cite journal |author=Ho PM, Maddox TM, Wang L, ''et al.'' |title=Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome |journal=JAMA |volume=301 |issue=9 |pages=937–44 |year=2009 |month=March |pmid=19258584 |doi=10.1001/jama.2009.261 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=19258584 |issn=}}</ref> (especially inhibitors other than [[pantoprazole]]<ref name="pmid19176635">Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8. Epub 2009 Jan 28. PMID 19176635</ref>) or may not<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref> increase adverse cardiac events.
CYP2C19 polymorphism affects response to [[clopidogrel]].  CYP2C19 loss-of-function alleles are associated with more cardiovascular events.<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref> Concomitant [[proton pump inhibitor]]s, which are also metabolized by CYP2C19, may<ref name="pmid19258584">{{cite journal |author=Ho PM, Maddox TM, Wang L, ''et al.'' |title=Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome |journal=JAMA |volume=301 |issue=9 |pages=937–44 |year=2009 |month=March |pmid=19258584 |doi=10.1001/jama.2009.261 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=19258584 |issn=}}</ref> (especially inhibitors other than [[pantoprazole]]<ref name="pmid19176635">Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8. Epub 2009 Jan 28. PMID 19176635</ref>) or may not<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref> increase adverse cardiac events.
===CYP2D6===
{{main|cytochrome P-450 CYP2D6}}
The [[cytochrome P-450 CYP2D6]] isoenzyme is abnormal in 3-10% of anglos and < 2% of asians and africans leading to poor metabolism of drugs that use the CYP2D6 [[isoenzyme]].<ref>{{OMIM|124030}}</ref><ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |month=November |pmid=11710893 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11710893 |issn=}}</ref><ref name="pmid12571261">{{cite journal |author=Weinshilboum R |title=Inheritance and drug response |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=529–37 |year=2003 |month=February |pmid=12571261 |doi=10.1056/NEJMra020021 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571261&promo=ONFLNS19 |issn=}}</ref>
Poor metabolism affects many [[antidepressant]]s, [[metoprolol]] and other drugs that use this [[isoenzyme]]. Some narcotics such as [[codeine]]<ref name="pmid8845855">{{cite journal| author=Sindrup SH, Brøsen K| title=The pharmacogenetics of codeine hypoalgesia. | journal=Pharmacogenetics | year= 1995 | volume= 5 | issue= 6 | pages= 335-46 | pmid=8845855
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8845855 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref> and [[oxycodone]]<ref name="pmid9871425">{{cite journal| author=Heiskanen T, Olkkola KT, Kalso E| title=Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. | journal=Clin Pharmacol Ther | year= 1998 | volume= 64 | issue= 6 | pages= 603-11 | pmid=9871425
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9871425 | doi=10.1016/S0009-9236(98)90051-0 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref> are metabolized by [[cytochrome P-450 CYP2D6]]. More information is available at Entrez Gene.<ref name="urlGene Home">{{cite web |url=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565 |title=Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6 [ Homo sapiens ] |author=Anonymous |authorlink= |coauthors= |date= |format= |work= |publisher=National Library of Medicine |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=2009-01-03}}</ref>
===CYP3A===
''CYP3A'' is an [[isoenzyme]] of cytochrome P-450.<ref>{{OMIM|124010}}</ref>
Simultaneous use of [[erythromycin]] and inhibitors of CYP3A may be associated with sudden cardiac death.<ref name="pmid15356306">{{cite journal |author=Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM |title=Oral erythromycin and the risk of sudden death from cardiac causes |journal=N. Engl. J. Med. |volume=351 |issue=11 |pages=1089–96 |year=2004 |month=September |pmid=15356306 |doi=10.1056/NEJMoa040582 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=15356306&promo=ONFLNS19 |issn=}}</ref>
==Testing==
Various tests are available to detect abnormal metabolism.<ref name="pmid19369936">{{cite journal |author=Flockhart DA, Skaar T, Berlin DS, Klein TE, Nguyen AT |title=Clinically available pharmacogenomics tests |journal=Clin. Pharmacol. Ther. |volume=86 |issue=1 |pages=109–13 |year=2009 |month=July |pmid=19369936 |doi=10.1038/clpt.2009.39 |url=http://www.nature.com/clpt/journal/v86/n1/full/clpt200939a.html |issn=}}</ref>
Examples are Affymetrix Targeted Human DMET (drug-metabolizing enzymes and  transporters).<ref name="pmid17324118">{{cite journal |author=Dumaual C, Miao X, Daly TM, ''et al.'' |title=Comprehensive assessment of metabolic enzyme and transporter genes using the Affymetrix Targeted Genotyping System |journal=Pharmacogenomics |volume=8 |issue=3 |pages=293–305 |year=2007 |month=March |pmid=17324118 |doi=10.2217/14622416.8.3.293 |url=http://www.futuremedicine.com/doi/abs/10.2217/14622416.8.3.293?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov |issn=}}</ref><ref name="pmid17510302">{{cite journal |author=Daly TM, Dumaual CM, Miao X, ''et al.'' |title=Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport |journal=Clin. Chem. |volume=53 |issue=7 |pages=1222–30 |year=2007 |month=July |pmid=17510302 |doi=10.1373/clinchem.2007.086348 |url=http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=17510302 |issn=}}</ref><ref name="urlAffymetrix - Drug Metabolizing Enzymes and Transporters (DMET) Plus - Campaign">{{cite web |url=http://www.affymetrix.com/promotions/dmet/drug_metabolizing_enymes_transporter.affx |title=Affymetrix - Drug Metabolizing Enzymes and Transporters (DMET) Plus - Campaign |author= |authorlink= |coauthors= |date= |format= |work= |publisher= |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=}}</ref> and AmpliChip CYP450 Test (tests CYP2D6 and CYP2C19 genes).<ref name="urlAmpliChip">{{cite web |url=http://www.amplichip.us/ |title=AmpliChip |author= |authorlink= |coauthors= |date= |format= |work= |publisher=Roche |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=}}</ref>
==References==
<references/>
==External links==
* [http://medicine.iupui.edu/flockhart/ Cytochrome p450 drug-interaction table]
* http://www.cypalleles.ki.se/

Revision as of 21:04, 9 October 2009

CYP2C19

CYP2C19 is an isoenzyme of cytochrome P-450.[1] 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 isoenzyme.[2][3] More recently, a study suggests that 30% of patients may have a reduced-function allele.[4]

CYP2C19 polymorphism affects response to clopidogrel. CYP2C19 loss-of-function alleles are associated with more cardiovascular events.[5] Concomitant proton pump inhibitors, which are also metabolized by CYP2C19, may[6] (especially inhibitors other than pantoprazole[7]) or may not[5] increase adverse cardiac events.

  1. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124020. World Wide Web URL: http://omim.org/.
  2. ↑ Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (November 2001). "Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review". JAMA 286 (18): 2270–9. PMID 11710893. [e]
  3. ↑ Weinshilboum R (February 2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
  4. ↑ Mega JL, Close SL, Wiviott SD, et al (December 2008). "Cytochrome P-450 Polymorphisms and Response to Clopidogrel". N. Engl. J. Med.. DOI:10.1056/NEJMoa0809171. PMID 19106084. Research Blogging.
  5. ↑ 5.0 5.1 Simon T, Verstuyft C, Mary-Krause M, et al. (January 2009). "Genetic determinants of response to clopidogrel and cardiovascular events". N. Engl. J. Med. 360 (4): 363–75. DOI:10.1056/NEJMoa0808227. PMID 19106083. Research Blogging.
  6. ↑ Ho PM, Maddox TM, Wang L, et al. (March 2009). "Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome". JAMA 301 (9): 937–44. DOI:10.1001/jama.2009.261. PMID 19258584. Research Blogging.
  7. ↑ Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8. Epub 2009 Jan 28. PMID 19176635
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