The diversity of the CYP2D6 gene is based on the polymorphisms of the CYP2D6 gene on chromosome 22 q13.1, because of mutations of these genes people can be broken down in four distinct variations, Poor Metabolisers (PM), Intermediate Metabolisers (IM), Extensive Metabolisers (EM) and Ultrarapid Metabolisers (UM) (Fig 1, Fig 2). The variations of this polymorphism that a person has will then directly correlate to the effects that a drug, which is a substrate for the CYP2D6 enzyme, will have.
Fig 1. The distribution of different forms of CYP2D6 in the Population (Apadpted from Service 2005)
Thanks to the successful and relatively simple methods of detection of polymorphisms in the CYP2D6 genes throughout a large population, where the antidepressant venlafaxine was used which is a substrate for the CYP2D6 enzyme and tested the serum concentrations of venlafaxine and its pharmacologically active metabolite O-desmethylvenlafaxine. This testing allowed for the ratio between the active metabolite and the CYP2D6 substrate venlafaxine to be calculated and use this as an indicator to the CYP2D6 phenotype with a higher ratio reflect a rapid metaboliser of the compound.
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Real-time PCR and quantative PCR were then also used for the identification and quantification of SNPâ€™s and deletions and or mutations in the gene sequence that leads to these variations in drug metabolism. (Borros Arneth et al, 2009)
Studies have been carried out to show how these variations can be correlated between different geographical locations and within different ethnicities. Due to the isolated tendencies of the Japanese population they are an ideal population for the study of genetic variations as many individuals will remain evolutionarily homologous.
Fig 2. CYP2D Gene Locus and Polymorphisms leading to enzyme efficacy variations.
The in vivo activity of CYP2D6 is functionally absent in 8% of Caucasians in Europe and North America, poor metabolizers (PMs), but fewer than 1% of Chinese or Japanese, resulting in different drug concentrations being required and responses to drugs in these racial groups (Tomonori Tateishi, 2002). The reason for this defect appears to be faulty expression of the cytochrome P450 protein, resulting in little or no isoform-catalyzed drug metabolism. A study of Taiwanese and mainland Chinese populations also indicated that there are inter-ethnic differences in the in vivo CYP2D6 activity between Asian populations.
In the Japanese study carried out 98 unrelated subjects were tested who were all unrelated and originated from different geographic locations of Japan. CYP2D6 * 18 and CYP2D6 * 21 mutatnts were shown to be present in poor metabolisers which as shown already are at very low levels in Asian communities ~1%. CYP2D6 * 2, which was reported in a subject with extremely high metabolic capacity of debrisoquine hydroxylation, was not detected in 12 subjects with the lowest activity (Fig 3).
Fig 3. Allele frequencies of CYP2D6 in the Japanese population studied (Tomonori Tateishi, 2002).
Thirty-three (33.7%) subjects were heterozygous for CYP2D6 * 10/CYP2D6 * 1, and 18 (18.4%) and 17 (17.3%) subjects were homozygous for CYP2D6 * 1 and CYP2D6 * 10, respectively. These three most common genotypes accounted for approximately 70% of the Japanese subjects. Among four major alleles, the influence of allelic combination on the activity which is shown by the log10 dextromethorphan MR was compared (Fig 4).
Fig 4. Allelic combination frequencies and the log10 dextromethorphan MR for each combination. (Tomonori Tateishi, 2002).
When comparing Japanese to Caucasians there has been a number of mutations in the gene that lead to the individual being a PM (Poor Metaboliser) these being CYP2D6 * 4 (15.6%), CYP2D6 * 5 (6.9%) and CYP2D6 * 3 (1.6%) (D Marez et al, 1997) which in comparison to the results of the Japanese study, there was only one individual ~1% that showed the CYP2D6 * 4 gene mutation. The other predominant gene in Caucasian individuals is CYP2D6 * 2 which when present is reported to be present in multiple (up to 13) gene copies in some subjects resulting in extremely high in vivo CYP2D6 activities identifying the person as a UM (Ultra rapid Metaboliser). The frequency of this mutation in Caucasians is thought to be ~25% while in the Japanese test population studies it showed to be only present in 9% of the subjects showing a much lower occourence of rapid metabolism in the Japanese community.
Despite the low frequency of a CYP2D6 PM in Asian populations, the mean of the distribution of the urinary metabolic ratio (MR) of debrisoquine/4-hydroxydebrisoquine of
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Extensive Metabolizers (EMs) among Chinese was shifted towards higher values compared to a Caucasian population as in Fig. 5
Fig. 1. Diagrammatic representations of the distribution of CYP2D6 substrate metabolic ratio in different populations including Caucasian, Japanese, Taiwanese and mainland Chinese. (Tomonori Tateishi, 2002).
Other studies have shown that variations do not only occur between ethnic groups but can occur dependant on diet, cultural habits, and primary language. This was shown in a study of different geographical Han populations in mainland China. Allele frequencies indicate that genetic composition also varies between the different geographical populations not just between ethnic groups. They found that only inactive alles CYP2D6*4, *5, and *14 were detected in Han population in comparison to the Caucasian population where CYP2D6*3, *4, *5, *6, *7, *15, and *16 were found to be present and inactive. They also gound that the frequency of certain specific alleles greatly varied in the Han population for example with CYP2D6*4 the frequency in the Caucasian population is 20.7%, 13.8% in the
Spanish , but 0.14% in the Han populations (Shengying Qin et al, 2008)
Fig 6. Comparison of CYP2D6 allele frequencies in different ethnic groups (Shengying Qin et al, 2008)
This broad and detailed systematic analysis of the polymorphisms of this gene in different ethnic and geographical subpopulations and a mapping of the polymorphism distribution over the worldwide population will be useful for personalized medicine in the population due to the number of xenobiotics that are broken down to their active component by the CYP2D6 enzymes.