• monooxygenase activity • iron ion binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • oxygen binding • heme binding • metal ion binding • unspecific monooxygenase activity
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.
The CYP2D6 function in any particular subject may be described as one of the following:
extensive metaboliser - these subjects have normal or reduced CYP2D6 function
poor metaboliser - these subjects have little or no CYP2D6 function
ultrarapid metaboliser - these subjects have multiple copies of the CYP2D6gene 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 (or CYP2C19) genotype.
Genetic basis of variability
The genetic basis for extensive and poor metaboliser variability is the CYP2D6allele, 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 (after Droll et al., 1998)
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%). In blacks, the frequency of poor metabolizers is greater than for whites (1.6% vs. 0.44%). The occurrence of CYP2D6 ultrarapid metabolisers appears to be greater amongst Middle Eastern and North African populations.
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 while approximately 50% of Asians possess the CYP2D6*10 allele, which should produce decreased CYP2D6 function; however this still appears to be within the normal range and are still grouped as extensive metabolisers.
^ Australian Medicines Handbook (AMH) 2004. ISBN 0-9578521-4-2
^ 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". Pharmacogenetics7 (3): 187–91. PMID 9241658.
^ ab 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". Pharmacogenetics8 (4): 325–33. PMID 9731719.
^ 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)
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