CYP2D6 explained

Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.

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, via the addition or removal of certain functional groups – specifically, hydroxylation, demethylation, and dealkylation.[1] CYP2D6 also activates some prodrugs. This enzyme also metabolizes several endogenous substances, such as N,N-Dimethyltryptamine, hydroxytryptamines, neurosteroids, and both m-tyramine and p-tyramine which CYP2D6 metabolizes into dopamine in the brain and liver.[1] [2] [3]

Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 substrates), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers). 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. So, the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.[4] Individuals who exhibit an ultrarapid metabolizer phenotype, metabolize prodrugs, such as codeine or tramadol, more rapidly, leading to higher than therapeutic levels.[5] [6] A case study of the death of an infant breastfed by an ultrarapid metabolizer mother taking codeine impacted postnatal pain relief clinical practices, but was later debunked.[7] These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as after tonsillectomy.[8] [9] [10] 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 as a second drug that is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a drug-drug interaction.[11]

Gene

The gene is located on chromosome 22q13.1. near two cytochrome P450 pseudogenes (CYP2D7P and CYP2D8P).[12] Among them, CYP2D7P originated from CYP2D6 in a stem lineage of great apes and humans,[13] the CYP2D8P originated from CYP2D6 in a stem lineage of Catarrhine and New World monkeys' stem lineage.[14] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[15]

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:[16]

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).[17]

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 (weak CYP2D6 function) 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 (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects.[18] Information about how human genetic variation of CYP2D6 affects response to medications can be found in databases such PharmGKB,[19] Clinical Pharmacogenetics Implementation Consortium (CPIC).[20]

Genetic basis of variability

The variability in metabolism is due to multiple different polymorphisms of 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.[21] The current known alleles of CYP2D6 and their clinical function can be found in databases such as PharmVar.[22]

CYP2D6 enzyme activity for selected alleles[23]
AlleleCYP2D6 activity
CYP2D6*1normal
CYP2D6*2normal
CYP2D6*3none
CYP2D6*4none
CYP2D6*5none
CYP2D6*6none
CYP2D6*7none
CYP2D6*8none
CYP2D6*9decreased
CYP2D6*10decreased
CYP2D6*11none
CYP2D6*12none
CYP2D6*13none
CYP2D6*14none
CYP2D6*15none
CYP2D6*17decreased
CYP2D6*19none
CYP2D6*20none
CYP2D6*21none
CYP2D6*27normal
CYP2D6*29decreased
CYP2D6*31none
CYP2D6*33normal
CYP2D6*38none
CYP2D6*40none
CYP2D6*41decreased
CYP2D6*42none
CYP2D6*44none
CYP2D6*47none
CYP2D6*50decreased
CYP2D6*51none
CYP2D6*68none
CYP2D6*92none
CYP2D6*100none
CYP2D6*101none
CYP2D6 duplicationincreased

Ethnic factors in variability

Ethnicity is a factor in the occurrence of CYP2D6 variability. The reduction of the liver cytochrome CYP2D6 enzyme occurs approximately in 7–10% in white populations, and is lower in most other ethnic groups such as Asians and African-Americans at 2% each. A complete lack of CYP2D6 enzyme activity, wherein the individual has two copies of the polymorphisms that result in no CYP2D6 activity at all, is said to be about 1-2% of the population.[24] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.[25] [26]

Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, producing extensive metabolism, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent.[27]

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 one (heterozygous) non-functional CYP2D6*4 allele,[28] 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:

Dopamine biosynthesis

Further reading

External links

Notes and References

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