Cytochrome P-450

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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]

Cytochrome P-450's role in drug metabolism is described by Wolf:[2]

"Nearly all lipophilic small molecules, including most drugs, which enter the body must be metabolised to more polar products before they can be excreted. This metabolic process, which is primarily catalysed by hepatic enzymes, consists of a sequence of enzymatic steps. This normally involves oxidation of the drug by the cytochrome P450-dependent monooxygenases (phase I metabolism), followed by conjugation involving sulphation, glucuronidation or acetylation (phase II metabolism)."

Common abnormal alleles

Common isoenzymes of cytochrome P-450
  Percentage of total human liver P450 content[3]
CYP1A2 15%
CYP2A6 4%
CYP2B6 1%
CYP2C9 20%
CYP2C19
CYP2D6 5%
CYP2E1 10%
CYP3A4 30%

Isoforms CYP2C9, CYP2C19, and CYP2D6 account for 40% of metabolism by Cytochrome P-450.[4]

CYP1A2

CYP1A2 is an isoenzyme of cytochrome P-450.[5] 12% of anglos are poor metabolizers of drugs that use the CYP1A2 isoenzyme.[6]

Slow metabolism may explain the association between caffeine and myocardial infarction.[7]

CYP2C9

CYP2C9 variants
Allele Nucleotide change
2 430C->T
3 1075A->C
4 1076T->C
5 1080C->G
6 818delA


CYP2C9 is an isoenzyme of cytochrome P-450.[8]2-6% of anglos are poor metabolizers of drugs that use the CYP2C9isoenzyme.[6][9]

Medications, such as the antilipemic agents atorvastatin, simvastatin, or gemfibrozil that are metabolized by this isoenzyme may increase bleeding when added to patients taking warfarin.[10]

Polymorphisms of CYP2C9 explain 10% of variation in warfarin dosing[11], mainly among Caucasian patients as these variants are rare in African American and most Asian populations.[12] A meta-analysis of mainly Caucasian patients found[12]:

  • 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

The antilipemic agent and clofibric acid derivative gemfibrozil, may interact with warfarin due to CYP2C9.[13] Antilipemic agents that are hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins), except for pravastatin and rosuvastatin, may also interact with warfarin, although this interaction is more likely due to CYP3A4.[10]

CYP2C19

For more information, see: cytochrome P-450 CYP2C19.

Cytochrome P-450 CYP2C19 is an isoenzyme of cytochrome P-450.[14] 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 isoenzyme.[6][9] More recently, a study suggests that 30% of patients may have a reduced-function allele.[15]

CYP2C19 polymorphism affects response to clopidogrel. CYP2C19 loss-of-function alleles are associated with more cardiovascular events.[16] Concomitant proton pump inhibitors, which are also metabolized by CYP2C19, may[17] (especially inhibitors other than pantoprazole[18]) or may not[16] increase adverse cardiac events.

CYP2D6

For more information, see: 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.[19][6][9]

Poor metabolism affects many antidepressants, metoprolol and other drugs that use this isoenzyme. Some narcotics such as codeine[20] and oxycodone[21] are metabolized by cytochrome P-450 CYP2D6. More information is available at Entrez Gene.[22]

CYP3A

CYP3A is an isoenzyme of cytochrome P-450.[23]

CYP3A4 may metabolize over 50% of prescription drugs that are metabolized by the liver.[3]

Simultaneous use of erythromycin and inhibitors of CYP3A may be associated with sudden cardiac death.[24] Simultaneous use of erythromycin and calcium channel blockers may cause hypotension.[25]

Antilipemic agents that are hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins), except for pravastatin and rosuvastatin, are metabolized by this isoenzyme and may:

Antibodies to isoenzymes

Anti-liver kidney microsome (LKM) antibodies may be present in Type 2 autoimmune hepatitis and other forms of chronic active hepatitis:[27][28]

Antibody Target Comment
ALKM-1 CYP2D6 type 2 autoimmune hepatitis
ALKM-2 CYP2C9  
ALKM-3 UDP glucuronosyltransferase  

Testing

Various tests are available to detect abnormal metabolism.[29]

Examples are Affymetrix Targeted Human DMET (drug-metabolizing enzymes and transporters).[30][31][32] and AmpliChip CYP450 Test (tests CYP2D6 and CYP2C19 genes).[33]

References

  1. Anonymous (2015), Cytochrome P-450 (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Wolf CR, Smith G (1999). "Pharmacogenetics.". Br Med Bull 55 (2): 366-86. PMID 10723863.
  3. 3.0 3.1 Correia, Maria Almira (2006). “Chapter 4. Drug Biotransformation”, Katzung, Bertram G.: Basic and Clinical Pharmacology, 10th. New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. 
  4. 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.
  5. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124060. World Wide Web URL: http://omim.org/.
  6. 6.0 6.1 6.2 6.3 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]
  7. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H (March 2006). "Coffee, CYP1A2 genotype, and risk of myocardial infarction". JAMA 295 (10): 1135–41. DOI:10.1001/jama.295.10.1135. PMID 16522833. Research Blogging.
  8. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 601130. World Wide Web URL: http://omim.org/.
  9. 9.0 9.1 9.2 Weinshilboum R (February 2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
  10. 10.0 10.1 10.2 Schelleman H, Bilker WB, Brensinger CM, Wan F, Yang YX, Hennessy S (2010). "Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk.". Am J Med 123 (2): 151-7. DOI:10.1016/j.amjmed.2009.07.020. PMID 20103024. PMC PMC2813204. Research Blogging.
  11. 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.
  12. 12.0 12.1 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]
  13. 13.0 13.1 Dixon DL, Williams VG (2009). "Interaction between gemfibrozil and warfarin: case report and review of the literature.". Pharmacotherapy 29 (6): 744-8. DOI:10.1592/phco.29.6.744. PMID 19476425. Research Blogging.
  14. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124020. World Wide Web URL: http://omim.org/.
  15. 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.
  16. 16.0 16.1 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.
  17. 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.
  18. 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
  19. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124030. World Wide Web URL: http://omim.org/.
  20. Sindrup SH, Brøsen K (1995). "The pharmacogenetics of codeine hypoalgesia.". Pharmacogenetics 5 (6): 335-46. PMID 8845855.
  21. Heiskanen T, Olkkola KT, Kalso E (1998). "Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.". Clin Pharmacol Ther 64 (6): 603-11. DOI:10.1016/S0009-9236(98)90051-0. PMID 9871425. Research Blogging.
  22. Anonymous. Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6 [ Homo sapiens ]. National Library of Medicine. Retrieved on 2009-01-03.
  23. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124010. World Wide Web URL: http://omim.org/.
  24. Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM (September 2004). "Oral erythromycin and the risk of sudden death from cardiac causes". N. Engl. J. Med. 351 (11): 1089–96. DOI:10.1056/NEJMoa040582. PMID 15356306. Research Blogging.
  25. Wright AJ, Gomes T, Mamdani MM, Horn JR, Juurlink DN (2011). "The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers.". CMAJ 183 (3): 303-7. DOI:10.1503/cmaj.100702. PMID 21242274. PMC PMC3042440. Research Blogging.
  26. Template:Err (2012 [last update]). Drug Safety and Availability > FDA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. fda.gov. Retrieved on March 2, 2012. “human immunodeficiency virus (HIV) or hepatitis C virus (HCV) known as protease inhibitors and certain cholesterol-lowering drugs known as statins. Protease inhibitors”
  27. Bogdanos DP, Mieli-Vergani G, Vergani D (2009). "Autoantibodies and their antigens in autoimmune hepatitis.". Semin Liver Dis 29 (3): 241-53. DOI:10.1055/s-0029-1233533. PMID 19675997. Research Blogging.
  28. Bogdanos DP, Dalekos GN (2008). "Enzymes as target antigens of liver-specific autoimmunity: the case of cytochromes P450s.". Curr Med Chem 15 (22): 2285-92. PMID 18781950.
  29. Flockhart DA, Skaar T, Berlin DS, Klein TE, Nguyen AT (July 2009). "Clinically available pharmacogenomics tests". Clin. Pharmacol. Ther. 86 (1): 109–13. DOI:10.1038/clpt.2009.39. PMID 19369936. Research Blogging.
  30. Dumaual C, Miao X, Daly TM, et al. (March 2007). "Comprehensive assessment of metabolic enzyme and transporter genes using the Affymetrix Targeted Genotyping System". Pharmacogenomics 8 (3): 293–305. DOI:10.2217/14622416.8.3.293. PMID 17324118. Research Blogging.
  31. Daly TM, Dumaual CM, Miao X, et al. (July 2007). "Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport". Clin. Chem. 53 (7): 1222–30. DOI:10.1373/clinchem.2007.086348. PMID 17510302. Research Blogging.
  32. Affymetrix - Drug Metabolizing Enzymes and Transporters (DMET) Plus - Campaign.
  33. AmpliChip. Roche.

External links