CYP2D6

CYP2D6
Cytochrome P450, family 2, subfamily D, polypeptide 6

PDB rendering based on 2f9q.
Identifiers
Symbols CYP2D6; CPD6; CYP2D; CYP2D7AP; CYP2D7BP; CYP2D7P2; CYP2D8P2; CYP2DL1; CYPIID6; MGC120389; MGC120390; P450-DB1; P450C2D; P450DB1
External IDs OMIM124030 MGI1929474 HomoloGene68036 GeneCards: CYP2D6 Gene
EC number 1.14.14.1
RNA expression pattern
PBB GE CYP2D6 207498 s at tn.png
PBB GE CYP2D6 215809 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1565 56448
Ensembl ENSG00000100197 ENSMUSG00000061740
UniProt P10635 n/a
RefSeq (mRNA) NM_000106.4 NM_019823
RefSeq (protein) NP_000097.2 NP_062797
Location (UCSC) Chr 22:
42.52 – 42.54 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. Also, many substances are bioactivated by CYP2D6 to form their active compounds. While 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]

Contents

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.

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.

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]

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.

CYP2D6 allele and enzyme activity[3]
Allele CYP2D6 activity
CYP2D6*1 normal
CYP2D6*2 increased
CYP2D6*3 none
CYP2D6*4 none
CYP2D6*5 none
CYP2D6*9 decreased
CYP2D6*10 decreased
CYP2D6*17 decreased

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 (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 among Middle Eastern and North African populations.[6]

This variability is accounted for by the differences in the prevalence of various CYP2D6 alleles among 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.

CYP2D6 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.[7]
  • Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.[7]
  • 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.[7]
Selected inducers, inhibitors and substrates of CYP2D6
Substrates
= bioactivation by CYP2D6
Inhibitors Inducers

strong:

Moderate

weak:

unspecified potency:

References

  1. ^ "Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565. 
  2. ^ Blake, M.J. et al. (2007). "Ontogeny of dextromethorphan O- and N-demethylation in the first year of life.". Clin. Pharmacol. Ther.. April (4) (81): 510–516. doi:10.1038/sj.clpt.6100101. PMID 17301735. 
  3. ^ a b c 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. doi:10.1097/00008571-199808000-00006. PMID 9731719. 
  4. ^ Australian Medicines Handbook (AMH) 2004. ISBN 0-9578521-4-2
  5. ^ Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002). "Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans". Clin. Pharmacol. Ther. 72 (1): 76–89. doi:10.1067/mcp.2002.125783. PMID 12152006. 
  6. ^ McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M (1997). "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians". Pharmacogenetics 7 (3): 187–91. doi:10.1097/00008571-199706000-00003. PMID 9241658. 
  7. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca cb cc cd ce cf cg Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. http://medicine.iupui.edu/flockhart/table.htm.  Retrieved on July 2011
  8. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare), retrieved July 2011
  9. ^ a b PHARMACOGENETICS AND PHARMACOGENOMICS. J. Steven Leeder PharmD, PhD Pediatric Clinics of North America - Volume 48, Issue 3 (June 2001). DOI: 10.1016/S0031-3955%2805%2970338-2.
  10. ^ Hoskins, J. M.; Carey, L. A.; McLeod, H. L. (2009). "CYP2D6 and tamoxifen: DNA matters in breast cancer". Nature Reviews Cancer 9 (8): 576. doi:10.1038/nrc2683. PMID 19629072.  edit
  11. ^ Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metab. Dispos. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12756210. 
  12. ^ a b c d e FASS, The Swedish official drug catalog > Kodein Recip Last reviewed 2008-04-08
  13. ^ Foster, B.C. et al. (2004). "In Vitro Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein ". Pharmaceutical Biology. 42 (2) (2): 159–169. doi:10.1080/13880200490512034. 
  14. ^ NIH-Inhibitory effects of H1-Antihistamines on CYP2D6

Further reading

External links



Wikimedia Foundation. 2010.

Игры ⚽ Нужно решить контрольную?

Look at other dictionaries:

  • CYP2D6 — Saltar a navegación, búsqueda Imagen tridimensional de la CYP2D6 CYP2D6 es el acrónimo de consenso internacional usado para referirse tanto a una enzima del citocromo P450 como al gen que regula la síntesis de la misma. Habitualmente al referirse …   Wikipedia Español

  • CYP2D6 — Cytochrome p450 Le cytochrome p450 (CYP) a une importance particulière en médecine et en pharmacie. En effet, cette enzyme est très impliquée dans la dégradation des molécules exogènes (xénobiotiques), en particulier des médicaments. Plus le… …   Wikipédia en Français

  • Codeine — For other uses, see Codeine (disambiguation). Codeine Systematic (IUPAC) name (5α,6α) 7,8 didehydro 4,5 epoxy 3 methoxy 17 methylmorphinan 6 ol Cli …   Wikipedia

  • Tamoxifen — Systematic (IUPAC) name (Z …   Wikipedia

  • Cytochrom-P450 — Molekülstruktur von Cytochrom P450eryF (PDB:1EGY) …   Deutsch Wikipedia

  • P450 — Cytochrom P450 Molekülstruktur von Cytochrom P450eryF (PDB:1EGY) …   Deutsch Wikipedia

  • Страттера — Действующее вещество ›› Атомоксетин* (Atomoxetine*) Латинское название Strattera АТХ: ›› N06BA09 Атомоксетин Фармакологическая группа: Адрено и симпатомиметики (альфа , бета ) Нозологическая классификация (МКБ 10) ›› F90.0 Нарушение активности и… …   Словарь медицинских препаратов

  • Dextromethorphan — Not to be confused with Dexamethasone. Dextromethorphan Systematic (IUP …   Wikipedia

  • Perhexiline — Drugbox IUPAC name = 2 (2,2 dicyclohexylethyl)piperidine CAS number=6621 47 2 ATC prefix=C08 ATC suffix=EX02 ATC supplemental= PubChem=4746 DrugBank= C=19 | H=35 | N=1 molecular weight = 277.488 bioavailability= Dose Dependent metabolism =… …   Wikipedia

  • Симбалта — Действующее вещество ›› Дулоксетин* (Duloxetine*) Латинское название Cymbalta АТХ: ›› N06AA Неселективные ингибиторы обратного захвата моноаминов Фармакологическая группа: Антидепрессанты Нозологическая классификация (МКБ 10) ›› F32 Депрессивный… …   Словарь медицинских препаратов

Share the article and excerpts

Direct link
Do a right-click on the link above
and select “Copy Link”