Cytochrome P450 2D6 (abbreviated CYP2D6) (EC 1.14.14.1), 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.

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:

• extensive metaboliser - these subjects have normal or reduced CYP2D6 function
• poor metaboliser - these subjects have no CYP2D6 function
• ultrarapid metaboliser - these subjects have multiple copies of the CYP2D6 gene expressed, and therefore greater-than-normal CYP2D6 function

The patients' 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. Genotype assays do not, however, give information on the phenotype and therefore cannot identify ultrarapid metabolisers.

Genetic basis of variability

The genetic basis for extensive and poor metaboliser variability is the CYP2D6 allele. Subjects who possess certain allelic variants will show normal, decreased or no CYP2D6 function depending on the allele.

Ethnic factors in variability

Furthermore ethnicity is a factor in the occurrence of CYP2D6 variability. The prevalence of CYP2D6 poor metabolisers is approximately 6-10% amongst Caucasian populations, but is lower in most other ethnic groups such as Asians (2%) (Rossi, 2004). The occurrence of CYP2D6 ultrarapid metabolisers appears to be greater amongst Middle Eastern and North African populations (McLellan et al., 1997).

This variability is accounted for by the differences in the prevalence of various CYP2D6 alleles amongst the populations. For example, appoximately 10% of Caucasians appear to have the non-functional CYP2D6*4 allele (Droll et al., 1998). Interestingly, the same study by Droll et al (1998) shows that 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.

CYP2D6 Ligands

References

• 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. PMID 9731719
• McLellan RA, Oscarson M, Seidegard J, Evans DA, Ingelman-Sundberg M (1997). Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 7 (3), 187-91. PMID 9241658
• Rossi S (Ed.) (2004). Australian Medicines Handbook (AMH) 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2

See also

• Caraco Y (2004). Genes and the response to drugs. New Engl J Med 351 (27), 2867-9. PMID 15625340