Cytochromes P450 enzymes are the highest impact among drug metabolizing enzymes, the major phase I enzymes including: CYP2C9, CYP2C19, and CYP2D6 are highly polymorphic and account together for about 40% of hepatic human phase I metabolism. CYP2D6 is responsible for about 25% of the metabolism of known drugs. The polymorphism of the CYP2D6 enzyme results in poor, intermediate, efficient or ultrarapid metabolizers (UMs) of CYP2D6 drugs. The polymorphism of this enzyme significantly affects the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. These polymorphisms, at ordinary drug doses, can either cause adverse drug reactions or no drug response.
A lack of CYP2D6 enzyme results in reduced effectiveness of drug therapy such as the analgesic effect of tramadol and codeine drugs. The CYP2D6 phenotype and genotype has been investigated with respect to the risk of suffering from different diseases with the PM phenotype predispose such as: different types of cancers, also with parkinsonism, Alzheimers disease, optic neuropathy, tremor, hair color, neuroleptic malignant syndrome, smoking behavior, opiate dependence, hematological neoplasias, and Lewy body disease, and others.
CYP2D6 gene is mapped to chromosome 22q13.2 and it encodes an enzyme of 497 amino acids. The variant CYP2D6 alleles can be classified into categories, which cause abolished, decreased, normal, increased or qualitatively altered catalytic activity. Among the most important variant are: CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*17, and CYP2D6*41. The most common in the world is CYP2D6*10 accounting for more than 50% of cases among Asians. CYP2D6*3, *4, *5, and *6 polymorphisms account for the majority of PMs and IMs, which are the most common non-functional alleles.
Evans et al. (1995) investigated the frequency of the CYP2D6 polymorphisms among Saudi Arabian and Filipino volunteers. The study included 102 healthy Saudis (92 males, 10 females) with an average age of 25 years. Two of the volunteers were found to have poor metabolism (PM) phenotype of dextromethorphan, while the other 100 were extensive metabolizers (EM). The population in this study resembled Orientals in the frequency of poor metabolizers of the dextromethorphan, with a frequency of the recessive allele 0.140.SE 0.049.
[See also: United Arab Emirates > Qumsieh et al., 2011].
Qumsieh et al. (2011) undertook a study to determine the frequencies of CYP2D6 alleles in the Emirati population using direct sequencing of all coding exons and large parts of the intronic sequences. A total of 151 Emiratis, including 50 healthy volunteers and 101 subjects on antidepressants, were included in this study. Overall, 17 alleles were identified in the study. Four new alleles and five new genotypes were also identified in this study. Apart from the new genotypes, the study also identified 44 previously reported genotypes in the Saudi population. Of these, 23 genotypes were of the EM phenotype, while 12 were classified as UM.
Kalow (1982) estimated the frequency of the poor hydroxylator phenotype to be about 1% in Arabs.
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