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 xenobiotics in the body. Whilst CYP2D6 is involved in the oxidation of a wide range of substrates of all the CYPs, there is considerable variability in its expression in the liver. The gene is located near two cytochrome P450 pseudogenes on chromosome 22q13.1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[1]
CYP2D6 activity was tested in "healthy infants receiving an oral dose (0.3 mg/kg) of dextromethorphan (DM) at 0.5, 1, 2, 4, 6, and 12 months of age. DM and its major metabolites were measured in urine. CYP2D6 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data indicated a strong correlation between CYP2D6 genotype and DM O-demethylation (beta=-0.638; 95% CI: -0.745, -0.532; P<0.001). CYP2D6 activity was detectable and concordant with genotype by 2 weeks of age, showed no relationship with gestational age, and did not change with post natal age up to 1 year. In contrast, DM N-demethylation developed significantly more slowly over the first year of life. Genotype and the temporal acquisition of drug biotransformation are critical determinants of a drug response in infants."[2]
Contents |
Genotype/phenotype variability
CYP2D6 shows the largest phenotypical variability amongst the CYPs, largely due to genetic 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:
- poor metaboliser - these subjects have little or no CYP2D6 function
- intermediate metabolizers - these subjects metabolize drugs at a rate somewhere between the poor and extensive metabolizers
- extensive metaboliser - these subjects have normal 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, which allows the automated determination of a patient's CYP2D6 (and 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.
| CYP2D6 allele and enzyme activity[3] | |
| Allele | CYP2D6 activity |
| CYP2D6*1 | normal |
| CYP2D6*2 | increased |
| CYP2D6*3 | none |
| CYP2D6*4 | none |
| CYP2D6*5 | none |
| CYP2D6*9 | decreased |
| CYP2D6*10 | decreased |
| CYP2D6*17 | 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 populations, but is lower in most other ethnic groups such as Asians (2%)[4]. In blacks, the frequency of poor metabolizers is greater than for whites[5]. The occurrence of CYP2D6 ultrarapid metabolisers appears to be greater amongst Middle Eastern and North African populations[6].
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,[3] while approximately 50% of Asians possess the CYP2D6*10 allele[3] which should produce decreased CYP2D6 function; however this still appears to be within the normal range and are still grouped as intermediate metabolisers.
CYP2D6 ligands
| Substrates | Inhibitors | Inducers |
|---|---|---|
major: [8]
minor:
|
strong: [9]
weak: unspecified:
|
strong:
moderate: unspecified: |
References
- ^ "Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565.
- ^ Blake, M.J. et al. (2007). "Ontogeny of dextromethorphan O- and N-demethylation in the first year of life.". Clin. Pharmacol. Ther. April (4) (81): 510-516. PMID 17301735.
- ^ a b c Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF (1998). "Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians". Pharmacogenetics 8 (4): 325–33. doi:10.1097/00008571-199808000-00006. PMID 9731719.
- ^ Australian Medicines Handbook (AMH) 2004. ISBN 0-9578521-4-2 [Amazon-US | Amazon-UK]
- ^ Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002). "Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans". Clin. Pharmacol. Ther. 72 (1): 76–89. doi:10.1067/mcp.2002.125783. PMID 12152006.
- ^ McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M (1997). "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians". Pharmacogenetics 7 (3): 187–91. doi:10.1097/00008571-199706000-00003. PMID 9241658.
- ^ Where classes of agents are listed, there may be exceptions within the class
- ^ Mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems
- ^ Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare)
- ^ http://www.ncbi.nlm.nih.gov/pubmed/12756210
Further reading
- Smith G, Stubbins MJ, Harries LW, Wolf CR (1999). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157.
- Wolf CR, Smith G (1999). "Cytochrome P450 CYP2D6". IARC Sci. Publ. (148): 209–29. PMID 10493260.
- Ding X, Kaminsky LS (2003). "Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts". Annu. Rev. Pharmacol. Toxicol. 43: 149–73. doi:10.1146/annurev.pharmtox.43.100901.140251. PMID 12171978.
- Lilienfeld S (2002). "Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease". CNS drug reviews 8 (2): 159–76. PMID 12177686.
- Yu AM, Idle JR, Gonzalez FJ (2004). "Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates". Drug Metab. Rev. 36 (2): 243–77. doi:10.1081/DMR-120034000. PMID 15237854.
External links
Open source encyclopedia content modification information:
This page was last modified on 6 March 2010 at 15:26.
Authorship and Review
Open source encyclopedia content provided here is not reviewed directly by MedLibrary.org. Content is sourced directly from Wikipedia and is authored by an open community of volunteers. It is not produced by or in any way affiliated with MedLibrary.org.
Usage Guidelines
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article on "CYP2D6", which is available in its original form here:
http://en.wikipedia.org/w/index.php?title=CYP2D6
All material adapted used from Wikipedia is available under the terms of the GNU Free Documentation License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.