Genetic polymorphisms of cytochrome P450-1A2 (CYP1A2) among Emiratis.

Mohammad M Al-Ahmad,Anne John,Subramanian Dhanasekaran,Naheed Amir,Salim M A Bastaki,Bassam R Ali,Yousef M Abdulrazzaq,Tomohiko Ai

doi:10.1371/journal.pone.0183424

Mohammad M Al-Ahmad, Anne John + Show 6 more

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https://doi.org/10.1371/journal.pone.0183424

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Journal: PloS one	Publication Date: Sep 21, 2017
Citations: 17	License type: CC BY 4.0

Affiliation: United Arab Emirates University

Abstract

Cytochrome P450 1A2 (CYP1A2) is one of the CYP450 mixed-function oxidase system that is of clinical importance due to the large number of drug interactions associated with its induction and inhibition. In addition, significant inter-individual differences in the elimination of drugs metabolized by CYP1A2 enzyme have been observed which are largely due to the highly polymorphic nature of CYP1A2 gene. However, there are limited studies on CYP1A2 phenotypes and CYP1A2 genotypes among Emiratis and thus this study was carried out to fill this gap. Five hundred and seventy six non-smoker Emirati subjects were asked to consume a soft drink containing caffeine (a non-toxic and reliable probe for predicting CYP1A2 phenotype) and then provide a buccal swab along with a spot urine sample. Taq-Man Real Time PCR was used to determine the CYP1A2 genotype of each individual. Phenotyping was carried out by analyzing the caffeine metabolites using High Performance Liquid Chromatography (HPLC) analysis. We found that 1.4%, 16.3% and 82.3% of the Emirati subjects were slow, intermediate and rapid CYP1A2 metabolizers, respectively. In addition, we found that 1.4% of the subjects were homozygote for derived alleles while 16.1% were heterozygote and 82.5% were homozygote for the ancestral allele. The genotype frequency of the ancestral allele, CYP1A2*1A/*1A, is the highest in this population, followed by CYP1A2 *1A/*1C and CYP1A2 *1A/*1K genotypes, with frequencies of 0.825, 0.102 and 0.058, respectively. The degree of phenotype/genotype concordance was equal to 81.6%. The CYP1A2*1C/*1C and CYP1A2*3/*3 genotypes showed significantly the lowest enzyme phenotypic activity. The frequency of slow activity CYP1A2 enzyme alleles is very low among Emiratis which correlates with the presence of low frequencies of derived alleles in CYP1A2 gene.

Highlights

The Cytochrome P450 1A2 (CYP1A2) enzyme, encoded by the CYP1A2 gene, is of important clinical interest due to the large number of drug interactions associated with its induction and inhibition
CYP1A2 is one of the major CYPs expressed in human liver constituting 13–15% of all CYPs while CYP2D6 represents only 2% of the total [4]
We found three different CYP1A2 derived alleles associated with slow activity

Summary

Introduction

CYP1A2 is an important enzyme that bioactivates a number of procarcinogens including polycyclic aromatic hydrocarbons, heterocyclic aromatic amines/amides, mycotoxins and some natural compounds such as aristolochic acids present in several Chinese herbal medicines. This enzyme metabolizes a large number of essential endogenous compounds including retinols, melatonin, steroids, uroporphyrinogen and arachidonic acids [2]. The CYP1A2 enzyme, encoded by the CYP1A2 gene, is of important clinical interest due to the large number of drug interactions associated with its induction and inhibition. More than 15 and 40-fold variations in mRNA and protein expression levels have been observed in the human liver with a significant number of inhibitors and inducers of expression [6]

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