Cytochrome P450 2D6 is an enzyme that in humans is encoded by the CYP2D6 gene.
CYP2D6 is primarily expressed in the liver.
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.
In particular, CYP2D6 is responsible for the metabolism and elimination of approximately
25% of clinically used drugs.
This enzyme also metabolizes several endogenous substances such as hydroxytryptamines and
neurosteroids.
There is considerable variation in the efficiency and amount of CYP2D6 enzyme produced between
individuals.
Hence for drugs that are metabolized by CYP2D6, certain individuals will eliminate these drugs
quickly while others slowly.
If a drug is metabolized too quickly, it may decrease the drug's efficacy while if the
drug is metabolized too slowly, toxicity may result.
Hence the dose of the drug may have to be adjusted to take into account of the speed
at which it is metabolized by CYP2D6.
In addition, other drugs may function as inhibitors of CYP2D6 activity or inducers of CYP2D6 enzyme
expression that will lead to decreased or increased CYP2D6 activity respectively.
If such a drug is taken at the same time a second drug who is a CYP2D6 substrate, the
first drug may affect the elimination rate of the second through what is known as a drug-drug
interaction.
Gene 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.
Genotype/phenotype variability CYP2D6 shows the largest phenotypical variability
among the CYPs, largely due to genetic polymorphism.
The genotype accounts for normal, reduced, and non-existent CYP2D6 function in subjects.
Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6
allele and have been shown to have widespread use in clinical practice.
The CYP2D6 function in any particular subject may be described as one of the following:
poor metabolizer – little or no CYP2D6 function intermediate metabolizers – metabolize drugs
at a rate somewhere between the poor and extensive metabolizers
extensive metabolizer – normal CYP2D6 function ultrarapid metabolizer – multiple copies
of the CYP2D6 gene are expressed, and therefore greater-than-normal CYP2D6 function
A patient's CYP2D6 phenotype is often clinically determined via the administration of debrisoquine
and subsequent plasma concentration assay of the debrisoquine metabolite.
The type of CYP2D6 function of an individual may influence the person's response to different
doses of drugs that CYP2D6 metabolizes.
The nature of the effect on the drug response depends not only on the type of CYP2D6 function,
but also on the extent to which processing of the drug by CYP2D6 results in a chemical
that has an effect that is similar, stronger, or weaker than the original drug, or no effect
at all.
For example, if CYP2D6 converts a drug that has a strong effect into a substance that
has a weaker effect, then poor metabolizers will have an exaggerated response to the drug
and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance
that has a greater effect than its parent chemical, then ultrarapid metabolizers will
have an exaggerated response to the drug and stronger side-effects.
Genetic basis of variability The genetic basis for extensive and poor metaboliser
variability is the CYP2D6 allele, located on chromosome 22.
Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6
function, depending on the allele.
Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6
allele and have been shown to have widespread use in clinical practice.
Ethnic factors in variability Ethnicity is a factor in the occurrence of
CYP2D6 variability.
The prevalence of CYP2D6 poor metabolizers is approximately 6–10% in white populations,
but is lower in most other ethnic groups such as Asians.
In African-Americans, the frequency of poor metabolizers is greater than for whites.
The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern
and North African populations.
This variability is accounted for by the differences in the prevalence of various CYP2D6 alleles
among the populations–approximately 10% of whites are intermediate metabolizers, due
to decreased CYP2D6 function, because they appear to have the non-functional CYP2D6*4
allele, while approximately 50% of Asians possess the decreased functioning CYP2D6*10
allele.
Ligands Following is a table of selected substrates,
inducers and inhibitors of CYP2D6.
Where classes of agents are listed, there may be exceptions within the class.
Inhibitors of CYP2D6 can be classified by their potency, such as:
Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC
values, or more than 80% decrease in clearance.
Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC
values, or 50-80% decrease in clearance.
Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase
in the plasma AUC values, or 20-50% decrease in clearance.
References
Further reading
External links Flockhart Lab Cyp2D6 Substrates Page at IUPUI
PharmGKB: Annotated PGx Gene Information for CYP2D6