CYP2C19 gene encodes for Cytochrome P450 2C19 enzyme, which is 490 amino acids long and weights 56 kDa. CYP2C19 is a member of cytochrome P450 superfamily of enzymes. CYPs are usually membrane-bound localize to the endoplasmic reticulum membrane or the inner mitochondrial. CYPs enzymes metabolize numerous substrates and have major role in drug interactions. CYP2C19 enzyme metabolizes many xenobiotics and therapeutic agents, including the anticonvulsive drug mephenytoin, omeprazole, propranolol, citalopram, imipramine, diazepam and some barbiturates.
The CYP2C19 gene consists of nine coding exons on chromosome 10q23 within a cluster of cytochrome P450; the transcript length is 1,901 bps. CYP2C19 polymorphisms are associated with variable ability to metabolize mephenytoin. Individuals can be either extensive metabolizers (EM) or poor metabolizers (PM). The PM phenotype shows an autosomal recessive pattern, while EM phenotype comprising both homozygous dominant and heterozygote genotypes. Poor metabolizers represent 2-5% of Caucasians and 13-23% of Asian populations.
There are different CYP2C19 alleles known such as: CYP2C19*1A CYP2C19*1B, CYP2C19*1C, CYP2C19*2A, CYP2C19*2B, CYP2C19*2C, CYP2C19*3A, and CYP2C19*3B. CYP2C19*2 and CYP2C19*3 alleles account for most of the PM alleles, CYP2C19*2 is characterized by G/A mutation in exon 5 that creates an aberrant splice site, while CYP2C19*3 is characterized by G/A mutation in exon 4, which results in a premature termination codon.
Samilchuk and Al-Awadi (1999) screened 165 unrelated Kuwaitis for the CYP2C19*2 and CYP2C19*3 polymorphisms. Thirty individuals carried the CYP2C19*2 polymorphism (28 heterozygous and 2 homozygous), while CYP2C19*3 was detected in only one individual. Samilchuk and Al-Awadi (1999) calculated the incidence of CYP2C19*2 variants to be 0.096 among the Kuwaiti population.
Luo et al. (2004) studied a Bedouin population consisting of 50 individuals. They identified the CYP2C19*3 gene in one Bedouin individual in a heterozygous state (CYP2C19*1/*3) while another had the CYP2C19*2 allele (linked with poor metabolism) in homozygous form.
Evans et al. (1995) studied the frequency of the CYP2C19 alleles among Saudi Arabian and Filipino volunteers. The study included 102 healthy Saudis (92 males, 10 females) with an average age of 25 years. Two Saudi volunteers were found to have poor metabolism (PM) phenotype, while the other 100 were extensive metabolizers (EM) of the S-mephenytoin. The frequency of the recessive allele among Saudis was 0.140.SE 0.049.
Al-Jenoobi et al. (2013) analyzed the genomic DNA of 192 healthy unrelated Saudi Arabian individuals to determine CYP2C19 polymorphism. Genotype frequency and allele frequency of the CYP2C19 variants CYP2C19*2, *3, *4, *6, *7 and *17 were noted. A total of 29 individuals (15.3%) were found to carry the heterozygous genotype of CYP2C19*2 and one individual (0.5%) was found to be homozygous for the defective allele. The allelic frequency of CYP2C19*2 was 8.2%. In the case of CYP2C19*17, 69 individuals (37.5%) were found to be heterozygous while 15 individuals (8.1%) were homozygous for the defective allele. The allelic frequency of CYP2C19*17 was 26.9%. The poor metabolizer alleles of CYP2C19*3, *4, *6 and *7 were not detected in the study. A previously unreported non-synonymous SNP G356A was discovered to have an allelic frequency of 50%. In-situ analysis predicted this SNP to be benign. Another rare SNP C336T was found to have an allelic frequency of 50.3%. Both SNPS were located in exon 3.