CYP2D6

Genotype predicted phenotype in Macedonians as well as Albanians and Romanies living in Macedonia:

UM: Ultrarapid metabolizer
EM: Extensive metabolizer
IM:  Intermediate metabolizer
PM:  Poor metabolizer

UM EM IM PM
Macedonians (%) 5 55 36 4
Albanians (%) 1 46 46 7
Romanies (%) 1 67 26 6

Genotyping Macedonians (n = 100), Albanians (n = 100) and Romanies (n = 100), obtained from the DNA bank of the Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov” at the Macedonian Academy of Science and Arts, Skopje, Republic of Macedonia (Kusmanovska et al., 2015).

The poor metabolizer genotype (*4/*5) was lower (0.2%) in Amerindians than in Mexican Mestizos (5%)
Ultrarapid metabolizer genotype was higher (12.6%) in indigenous groups than in Mexican Mestizos (7%)

The most frequent alleles were:
CYP2D6*2 (0.05–0.28),
CYP2D6*4 (0.003–0.21)
multiplications (0.043–0.107).


CYP2D6*5, *6, *10 and *41 were not observed in the majority of Amerindians,
CYP2D6*3, *17, *35 and *29 were not detected.

(N=508 Amerindians;
129 Tepehuanos, 107 Huicholes and 39 Mexicaneros from the state of Durango;
74 Tarahumaras from the state of Chihuahua;
81 Coras from the state of Nayarit;
19 Seris, 15 Guarijíos and 44 Mayos from the state of Sonora.)

Lazalde-Ramos et al., 2014

CYP2D6 (measured phenotype):
92.0 % extensive metabolizers
8.0 % poor metabolizers
(N=4301, Dutch healthy volunteers,  98.9% Caucasian, 68% males)(Tamminga et al., 1999).
[Note editor: Study-population is allocated to two categories: extensive or poor metabolizers; superextensive and slow metabolizers are not mentioned. Apparently extensive and superextensive are lumped together into ‘extensive metabolizers’ and slow and poor metabolizers into ‘poor metabolizers’]

CYP 2D6

CYP2D6 substrates:

amitriptyline   doxepine  paroxetine 
aripiprazole duloxetine risperidone
clomipramine  fluoxetine thioridazine 
codeine haloperidol tramadol
desipramine imipramine  venlafaxine

 

Source: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). "http://medicine.iupui.edu/clinpharm/ddis/clinical-table/"

 

CYP2D6 basic facts:

Cytochrome P450 2D6 (or CYP2D6) is a drug-metabolizing enzyme involved in the first phase metabolism of around 25% of the drugs commonly used in clinical practice (Ingelman-Sundberg, 2005; Llerena et al. 2014). This enzyme is encoded by the CYP2D6 gene located on chromosome 22. The CYP2D6 gene is polymorphic, at this moment more than 130 allelic variants have been described (an overview can be found at http://www.cypalleles.ki.se/cyp2d6.htm). CYP2D6 variants as CYP2D6*3, *4, *5 or *6 are considered nonfunctioning variants. CYP2D6*10, *17, *29 or *41 are partially functioning variants, whereas the duplication/multiplication of active alleles (CYP2D6*1xN, *2xN) are related to increased activity (Llerena et al. 2014). Subjects show (this is a classification often used in the scientific literature) normal function (EM: extensive metabolizers), decreased function (IM or SM: intermediate or slow metabolizers), no function (PM: poor metabolizers) or (much) greater function of CYP2D6-mediated metabolic activity (UM of SEM: utrarapid metabolizers or superextensive metabolizers). Although there is not a one-to-one relationship between genotype and phenotype, the above mentioned classification is highly correlated with the kind of allelic variants people posess. Llerena et al. 2014 calculated the correlation between the frequencies of CYP2D6 genetically expected PMs and the phenotypically measured PMs and found a very high correlation by ethnic group (r = 0.869, p < 0.001) and an even higher correlation by geographic region (r = 0.936, p = 0.006). This indicates a very close relationship between genotype and phenotype.

Interethnic variability around the world:

CYP2D6*1 allele (the 'wild type', fully functional) and CYP2D6*2 are the predominant alleles worldwide, followed by CYP2D6*10 (19.05%) and CYP2D6*4 (11.32%) (Llerena et al. 2014).

CYP2D6*4 (nonfunctioning variant) is more frequent in Europe and Caucasians around the world.

CYP2D6*10 (partially functioning variant) is most frequent in Asia and East Asians.

CYP2D6*17 and *29 (both associated with reduced enzyme activity) are most frequent in Africa and Black populations around the world.

CYP2D6*41 (partially functioning) and CYP2D6-multiplications (associated with ultrarapid metabolism) are most frequent in Middle East populations.

Predicted poor metabolisers (based on the genotype) as well as the actual phenotypically poor metabolizers are more frequent in Europe and Caucasians.

The highest frequency of genetically predicted ultra-rapid metabolizers is found in Middle Easterns populations and Ethiopians.

(These findings are derived from a high quality systematic review by Llerena et al. 2014. Their analysis included 44,572 individuals studied in 172 original research papers).

 

Cytochrome P450 2D6 structure by BorisTM, 2016

CYP2D6 structure

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