Cytochrome P450, family 2, subfamily D, polypeptide 6
PDB rendering based on 2f9q.
Available structures PDB 2f9q
Identifiers
Symbols	CYP2D6; CYP2D; CYP2D@; P450C2D; CPD6; CYP2DL1; MGC120389; MGC120390; P450-DB1
External IDs	OMIM: 124030 MGI: 1929474 HomoloGene: 68036 GeneCards: CYP2D6 Gene
Gene Ontology Molecular function • 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 Cellular component • endoplasmic reticulum • microsome • membrane Biological process • electron transport Sources: Amigo / EGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1565	56448
Ensembl	ENSG00000100197	ENSMUSG00000061740
UniProt	P10635	n/a
RefSeq (mRNA)	NM_000106	NM_019823
RefSeq (protein)	NP_000097	NP_062797
Location (UCSC)	Chr 22: 40.85 - 40.86 Mb	Chr 15: 82.2 - 82.21 Mb
PubMed search	[1]	[2]

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]

[edit] 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.

[edit] 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.

[edit] 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.

[edit] CYP2D6 ligands

[edit] References

[edit] Further reading

[edit] External links

• Flockhart Lab Cyp2D6 Substrates Page at IUPUI
• PharmGKB: Annotated PGx Gene Information for CYP2D6

v • d • e PDB Gallery 2f9q: Crystal Structure of Human Cytochrome P450 2D6

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "CYP2D6".