3 Mol. Med. Comm. 01 (01) 2021, 03-16 Molecular Medicine Communications DOI: 10.12345/mmc.001.01.0016 Research Article Polymorphisms in CYP2C8 Gene in Pakistani population and their frequencies in various ethnic groups Rosana Christine 1 , Cavalcanti Ximenes 1 , Bashir Ahmad 2 , Vahid Nikoui 3 , Khuseyn Egamnazarov 4 , Muhammad Imran Khan 5* 1 Neuropsychiatry and Behavioral Sciences Graduate Program, Federal University of Pernambuco, Recife, Brazil 2 Department of Physiology, Bannu Medical College, Bannu, Pakistan 3 Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran 4 Department of environmental health, State Educational Institution “Avicenna Tajik State Medical University”, Dushanbe, the Republic of Tajikistan. 5 Department of Biomedical Sciences, Pak-Austria Fachhochschule: Institute of Applied Sciences and Technology, PKP, Pakistan *Correspondence: mik9892@gmail.com © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Abstract Cytochrome P4502C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in the metabolism of endogenous compounds. More than 20 single nucleotide polymorphisms (SNPs) have been reported, mainly in exon 3, 5, and 8. Some of the SNP’s lead to decreased enzyme activity and may have impact on drug metabolism. This research study aims to determine the frequencies of the most common SNPs of the CYP2C8 gene (CYP2C8*2, *3, *4) in the Pakistani population. A cross-sectional study consisting of 391 healthy humans was conducted after taking informed consent. DNA was extracted using commercial kits, and allelic and genotype frequencies were determined after PCR amplification, restriction fragment length polymorphism, and gel electrophoresis. The rate of minor allele was found to be 11.64% for CYP2C8*2, 14.71% for CYP2C8*3, and 1.53% for CYP2C8*4. Comparison with the 1000 Genome project reveals that the allelic frequencies of CYP2C8*4 in Pakistani population were similar to other South Asian populations while the frequencies of CYP2C8*2 and CYP2C8*3 as significantly different from other South Asian populations. A significant interethnic variation was also observed among Pakistani ethnicities. The CYP2C8*2 allele was highest in the Sindhi population, CYP2C8*3 in the Pashtoon population and CYP2C8*4 in the Balochi population. These data suggest that the frequency of poor metabolizers of CYP2C8 is high enough in the Pakistani population to warrant further genotype- phenotype correlations studies on individual drugs metabolized by CYP2C8 enzyme. Keywords: CYP2C8, poor metabolizer, non-responder phenomenon, Pakistan, Genetic polymorphism Introduction A significant number of drugs, xenobiotics, and endogenous compounds are metabolized by the cytochrome P450 (CYP) enzyme superfamily (Zanger and Schwab 2013). The enzyme originated about three billion years ago, are found in a large variety of members of the animal kingdom (Danielson 2002). In human beings, the CYP2C subfamily represents approximately 18-30% of the total cytochrome enzymes (Goldstein 2001). Taking up about 6-7% of the entire hepatic cytochrome enzyme content (Achour, Barber, and Rostami-Hodjegan 2014; Inoue et al. 2006; Rostami- Hodjegan and Tucker 2007), the CYP2C8 enzyme is a crucial member of this subfamily and is also responsible for metabolizing over a 100 clinical drugs currently used (Minhas et al. 2013). Moreover, different ethnic groups have shown a distinct spectrum of single nucleotide polymorphisms (SNPs) in the CYP2C8 gene. These variations have been studied in populations