Cytochrome P450 2D6 (CYP2D6) is anenzyme that in humans is encoded by theCYP2D6gene.CYP2D6 is primarily expressed in theliver. It is also highly expressed in areas of thecentral nervous system, including thesubstantia nigra.
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 CYP2D6substrates), 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'sefficacy while if the drug is metabolized too slowly, toxicity may result.[8] 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.[9] Individuals who exhibit an ultrarapid metabolizer phenotype, metabolizeprodrugs, such ascodeine ortramadol, more rapidly, leading to higher than therapeutic levels.[10][11] 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.[12] These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as aftertonsillectomy.[13][14][15] Other drugs may function asinhibitors of CYP2D6 activity orinducers 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 adrug-drug interaction.[8]
The gene is located onchromosome 22q13.1. near two cytochrome P450pseudogenes (CYP2D7P and CYP2D8P).[16] Among them, CYP2D7P originated from CYP2D6 in a stem lineage of great apes and humans,[17] the CYP2D8P originated from CYP2D6 in a stem lineage ofCatarrhine andNew World monkeys' stem lineage.[18]Alternatively spliced transcript variants encoding differentisoforms have been found for this gene.[19]
CYP2D6 shows the largestphenotypical variability among the CYPs, largely due togeneticpolymorphism. Thegenotype 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.[20]The CYP2D6 function in any particular subject may be described as one of the following:[21]
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 theCYP2D6 gene are expressed, so greater-than-normal CYP2D6 function occurs
A patient's CYP2D6 phenotype is often clinically determined via the administration ofdebrisoquine (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquinemetabolite (4-hydroxydebrisoquine).[22]
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.[23] Information about how human genetic variation of CYP2D6 affects response to medications can be found in databases such PharmGKB,[24] Clinical Pharmacogenetics Implementation Consortium (CPIC).[25]
The variability in metabolism is due to multiple differentpolymorphisms of theCYP2D6allele, located onchromosome 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.[20] The current known alleles of CYP2D6 and their clinical function can be found in databases such as PharmVar.[26]
Ethnicity is a factor in the occurrence of CYP2D6 variability. The reduction of the liver cytochrome CYP2D6 enzyme occurs approximately in 7–10% inwhite populations, and is lower in most other ethnic groups such asAsians andAfrican-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.[27] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater amongMiddle Eastern andNorth African populations.[28][29] InEthiopia, a particularly high percentage (30%) of the population are ultrametabolizers. As a result, the analgesic codeine is banned in Ethiopia due to the high rate of adverse events associated with ultrarapid metabolism of codeine in this population.[30]
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.[31]
This variability is accounted for by the differences in the prevalence of variousCYP2D6 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-functionalCYP2D6*4 allele,[32] while approximately 50% of Asians possess the decreased functioningCYP2D6*10 allele.[32]
Following is a table of selectedsubstrates,inducers andinhibitors of CYP2D6. Where classes of agents are listed, there may be exceptions within the class.
Inhibitors of CYP2D6 can be classified by theirpotency, such as:
Strong inhibitor being one that causes at least a 5-fold increase in the plasmaAUC values of sensitive substrates metabolized through CYP2D6, or more than 80% decrease inclearance thereof.[33]
Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP2D6, or 50-80% decrease in clearance thereof.[33]
Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP2D6, or 20-50% decrease in clearance thereof.[33]
Selected inducers, inhibitors and substrates of CYP2D6
In humans,catecholamines and phenethylaminergictrace amines are derived from the amino acidphenylalanine. It is well established that dopamine is produced from L-tyrosine via L-dopa; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from L-tyrosine viap-tyramine.[44] Similarly, CYP2D6 also metabolizesm-tyramine into dopamine.[44]
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