Tamkeen Fatima, Farah Zeb and Ahsana Dar Farooq* Pages 172 - 181 ( 10 )
Background: In the human population, CYP2D6 is highly polymorphic group of genes involved in metabolizing ~25% of all clinically used neuroleptic and antidepressant drugs. The CYP2D6*4 and CYP2D6*10 variants are prevalent in Asian population exhibiting variable drug metabolizing ability thereby affecting drug therapeutic responses.
Objective: To determine the genotypic frequencies of CYP2D6*1 (Normal metabolizer), *4 (Poor metabolizer) and *10 (Intermediate metabolizer) variants among schizophrenic subjects and control group from a sub-set of Karachi population.
Method: Genomic Deoxyribonucleic Acid (gDNA) was extracted and amplified with CYP2D6*4 and *10 primers using Polymerase Chain Reaction (PCR) and digested by Bacillus stereothermophilus (BstN1) and Hemophilus parahemolyticus (Hph1) restriction enzymes. The digested gDNA bands were identified as wild type or mutants and their genotypic frequencies were estimated by Hardy-Weinberg Equation (HWE).
Results: In normal subjects, frequencies of CYP2D6*1 wild allele (57%) coded functional enzyme, CYP2D6*4 variant (9%) producing non-functional enzyme and CYP2D6*10 allele (70%) producing altered enzyme with reduced activity that was most prevalent in schizophrenic patients.
Discussion: Drug response is a complex phenomenon that is governed by genetic and environmental factors. Antipsychotic drug metabolism among schizophrenic patients with variable drug responsesis related to CYP2D6 polymorphism. Clinically, it is imperative to differentiate between responders and non-responders using the treatment, otherwise the drug will be either nonefficacious or toxic to the patients. Therefore, a gene testing system needs to be established to identify patient’s genotype(s) predicting whether they are normal, poor, intermediate or ultrarapid drug metabolizer thereby allowing clinicians to adjust dose(s) of antipsychotic drug(s).
Conclusion: Genotyping of CYP2D6 alleles among schizophrenic patients indicated prevalence of *4 and *10 variants in Karachi population producing non-functional (poor metabolizer) and reduced functional (intermediate metabolizer) drug metabolizing enzymes phenotypes, respectively. Hence, dose adjustment is crucial otherwise schizophrenia condition will not be improved satisfactorily. Therefore, CYP2D6 gene screening program should be included in clinical practice to help clinicians to prescribe appropriate doses according to patient’s genotype and minimize sufferings of schizophrenics including side effects of drug that might occur at high drug concentrations.
Schizophrenia, CYP2D6 alleles, genotyping, gene frequency, Karachi population, Genomic Deoxyribonucleic Acid (gDNA).
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pharmacology Section, H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pharmacology Section, H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi