Cytochrome P-450: Difference between revisions

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imported>Robert Badgett
imported>Robert Badgett
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==Common abnormal alleles==
==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>
===CYP2C9===
===CYP2C9===
''CYP2C9'' is an [[isoenzyme]] of cytochrome P-450.<ref>{{OMIM|601130}}</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'' is an [[isoenzyme]] of cytochrome P-450.<ref>{{OMIM|601130}}</ref>2-6% of anglos are poor metabolizers 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>
 
[[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:
* CYP2C9*2 allele:
** present in 12.2% of patients
** present in 12.2% of patients
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===CYP2C19===
===CYP2C19===
CYP2C19 polymorphism affects response to [[clopidogrel]]. 30% of patients may have a reduced-function allele.<ref>{{OMIM|124020}}</ref><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 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> 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]]. 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>


===CYP2D6===
===CYP2D6===
3-10% of anglos are poor metabolizers 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> This affects many [[antidepressant]]s, [[metoprolol]] and other drugs that use this [[isoenzyme]]. 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>
3-10% of anglos and < 2% of asians and africans are poor metabolizers 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]]. 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>


==References==
==References==

Revision as of 10:28, 8 July 2009

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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 steroids, 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."[1]

Common abnormal alleles

Isoforms CYP2C9, CYP2C19, and CYP2D6 account for 40% of metabolism by Cytochrome P-450.[2]

CYP2C9

CYP2C9 is an isoenzyme of cytochrome P-450.[3]2-6% of anglos are poor metabolizers of drugs that use the CYP2D6 isoenzyme.[4][5][6]

Polymorphisms of CYP2C9 explain 10% of variation in warfarin dosing[7], mainly among Caucasian patients as these variants are rare in African American and most Asian populations.[8] A meta-analysis of mainly Caucasian patients found[8]:

  • 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 is an isoenzyme of cytochrome P-450.[9] 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2D6 isoenzyme.[10][5][6] More recently, a study suggests that 30% of patients may have a reduced-function allele.[11]

CYP2C19 polymorphism affects response to clopidogrel. 30% of patients may have a reduced-function allele.[11]

CYP2D6

3-10% of anglos and < 2% of asians and africans are poor metabolizers of drugs that use the CYP2D6 isoenzyme.[12][5][6]

Poor metabolism affects many antidepressants, metoprolol and other drugs that use this isoenzyme. More information is available at Entrez Gene.[13]

References

  1. ↑ Anonymous (2024), Cytochrome P-450 (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. ↑ Caraco Y (December 2004). "Genes and the response to drugs". N. Engl. J. Med. 351 (27): 2867–9. DOI:10.1056/NEJMe048278. PMID 15625340. Research Blogging.
  3. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 601130. World Wide Web URL: http://omim.org/.
  4. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124030. World Wide Web URL: http://omim.org/.
  5. ↑ 5.0 5.1 5.2 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]
  6. ↑ 6.0 6.1 6.2 Weinshilboum R (February 2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
  7. ↑ Wadelius M, Chen LY, Downes K, et al (2005). "Common VKORC1 and GGCX polymorphisms associated with warfarin dose". Pharmacogenomics J. 5 (4): 262-70. DOI:10.1038/sj.tpj.6500313. PMID 15883587. Research Blogging.
  8. ↑ 8.0 8.1 Sanderson S, Emery J, Higgins J (2005). "CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis". Genet. Med. 7 (2): 97-104. PMID 15714076. [e]
  9. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124020. World Wide Web URL: http://omim.org/.
  10. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124030. World Wide Web URL: http://omim.org/.
  11. ↑ 11.0 11.1 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.
  12. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124030. World Wide Web URL: http://omim.org/.
  13. ↑ Anonymous. Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6 [ Homo sapiens ]. National Library of Medicine. Retrieved on 2009-01-03.

External links

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