scholarly journals Genetic variations in the drug metabolizing enzyme, CYP2E1, among various ethnic populations of Pakistan

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9721
Author(s):  
Sagheer Ahmed ◽  
Nadeem Altaf ◽  
Mahnoor Ejaz ◽  
Zaira Zulfiqar ◽  
Kholood Janjua ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Adverse Effects ◽  
Drug Response ◽  
Variable Response ◽  
Healthy Human ◽  
Pakistani Population ◽  
Drug Metabolizing Enzyme ◽  
Different Populations ◽  
Metabolizing Enzyme ◽  
Low Activity

Genetic polymorphism in cytochrome P450 (CYP) monooxygenase genes is an important source of interindividual variability of drug response. CYP enzyme activities may change as a result of such polymorphisms which then, may affect drug metabolism. This would result in a change in the severity and frequency of adverse effects in addition to the non-responder phenomenon. CYP2E1, a member of CYP superfamily, affects the metabolism of several clinically important drugs such as halothane, paracetamol, etc. Genetic variation in CYP2E1 is known to cause significant inter-individual differences in drug response and adverse effects. The degree of genetic variation is found to be different in different populations around the world. The frequencies of two important polymorphisms in the CYP2E1*7C, NC_000010.10:g.135340548A>G (rs2070672) and CYP2E1, NC_000010.10:g.135339244G>C (rs3813865), are not known in the Pakistani population. In the present investigation, 636 healthy human volunteers were screened for these two single nucleotide polymorphism. Our results indicate that about 18% (rs2070672) and 28% (rs3813865) of the Pakistani population has a genotype containing at least one low activity allele. A significant interethnic variation in the frequencies of both the polymorphisms was observed. These results suggest that pharmacogenetics screening for low activity genotypes would be a helpful tool for clinicians when they prescribe medications metabolized by CYP2E1, as a significant fraction of the Pakistani population is expected to have a variable response to these drugs.

scholarly journals Variations in the frequencies of polymorphisms in the CYP2C9 gene in six major ethnicities of Pakistan

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sagheer Ahmed ◽  
Nadeem Altaf ◽  
Mahnoor Ejaz ◽  
Aisha Altaf ◽  
Aneela Amin ◽  
...  
Keyword(s):  
Ethnic Groups ◽  
South Asian ◽  
Drug Response ◽  
Wild Type ◽  
Healthy Human ◽  
Pakistani Population ◽  
Human Volunteers ◽  
Cyp2c9 Gene ◽  
Written Informed Consent ◽  
Low Activity

Abstract Genetic variation in cytochrome P450 (CYP) 2C9 is known to cause significant inter-individual differences in drug response and adverse effects. The frequencies of CYP2C9*2 and CYP2C9*3, both of which are responsible for the low activity of the enzyme, are not known in the Pakistani population. Therefore, we screened various ethnic groups residing in Pakistan for these polymorphisms. A total of 467 healthy human volunteers were recruited from six major ethnicities of Pakistan after written informed consent. Our results indicate that about 20% of the Pakistani population has a genotype containing at least one low activity allele. Ethnic Punjabi and Pathan populations had the highest frequencies of wild type genotypes while Urdu, Seraiki, and Sindhi populations showed higher rates of both low activity genotypes. The Baloch population showed the highest rates of low activity genotypes with less than 50% of the samples showing wild type genotypes, suggesting that more than half of the Baloch population possesses low activity genotypes. The frequencies found in various ethnic groups in Pakistan were comparable with ethnicities in the South Asian region except for the Baloch population. These results suggest that pharmacogenetics screening for low activity genotypes may be a helpful tool for clinicians while prescribing medications metabolized by CYP2C9.

Transcription Factor and Drug-Metabolizing Enzyme Gene Expression in Lymphocytes from Healthy Human Subjects

2007 ◽  
Vol 36 (1) ◽  
pp. 182-189 ◽  
Author(s):  
Gérard Siest ◽  
Elise Jeannesson ◽  
Jean-Brice Marteau ◽  
Anastasia Samara ◽  
Bérangère Marie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Human Subjects ◽  
Healthy Human ◽  
Enzyme Gene ◽  
Drug Metabolizing Enzyme ◽  
Healthy Human Subjects ◽  
Metabolizing Enzyme

scholarly journals Signatures of natural selection in the drug metabolizing enzyme genes: Opportunity for developing personalized and precision medicine

2017 ◽  
Author(s):  
Sheikh Nizamuddin ◽  
K. Thangaraj
Keyword(s):  
Natural Selection ◽  
Drug Response ◽  
Modern Human ◽  
Beta Agonist ◽  
P Value ◽  
Q Value ◽  
Drug Metabolizing Enzyme ◽  
Comprehensive Information ◽  
Other World ◽  
Metabolizing Enzyme

AbstractModern human experienced various selective pressures; including range of xenobiotics which contributed to heterogeneity of drug response. Many genes involve in pharmacokinetics and dynamics of drug, have been reported under natural selection. However, none of the studies have utilized comprehensive information of drug-centered PharmGKB pathways. We have extended this work and aimed to investigate sweep signals, using 1,798 subjects, from 53 Indian and 15 other world populations. We observed that modifiers which alters the biochemical function of other genes, have excess of natural selection (median std-z score=0.033±0.95; p-value=1.7×10−9-3.7×10−3). Taxane and statin primarily used for chemotherapy and lowering cholesterol level, respectively; and well known for heterogeneous drug response. We observed that pharmacokinetic pathway of taxane and statins are under natural selection (p-value=2.53×10−9and 2.73×10−9-1.09×10−4; q-value=1.28×10−7 and 6.91×10−6-1.1×10−3). We also observed signal of selection in Ibuprofen pharmacokinetics (p-value=1.76×10−5; q-value =2.22×10−4), beta-agonist/beta-blocker pharmacodynamics (p-value=4.79×10−4; q-value =4.04×10−4) and Zidovudin pharmacokinetics/dynamic pathway (p-value=7.0×10−4; q-value =5.06×10−4). Hard sweeps signals were observed in a total of 322 loci. Of which, 53 affect mRNA expression (p-value<0.001) and 16 were already reported with therapeutic response. Interestingly, we observed that Africans have experience 2 phases of natural selection, one at ~30,000 another at ~10,000 years before present.

scholarly journals Population genetic approaches to neurological disease: Parkinson's disease as an example

2005 ◽  
Vol 360 (1460) ◽  
pp. 1573-1578 ◽  
Author(s):  
S Gandhi ◽  
P.M Abou-Sleiman ◽  
D.G Healy ◽  
M Weale ◽  
W Gilks ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Xenobiotic Enzymes ◽  
Drug Metabolizing Enzyme ◽  
Gene Environment ◽  
Tremendous Progress ◽  
Different Populations ◽  
Metabolizing Enzyme

Parkinson's disease (PD) is a common, progressive, incurable disabling condition. The cause is unknown but over the past few years tremendous progress in our understanding of the genetic bases of this condition has been made. To date, this has almost exclusively come from the study of relatively rare Mendelian forms of the disease and there are no currently, widely accepted common variants known to increase susceptibility. The role that the ‘Mendelian’ genes play in common sporadic forms of PD is unknown. Moreover, most studies in PD can really be described as candidate polymorphism studies rather than true and complete assessments of the genes themselves. We provide a model of how one might tackle some of these issues using Parkinson's disease as an illustration. One of the emerging hypotheses of gene environment interaction in Parkinson's disease is based on drug metabolizing (or xenobiotic) enzymes and their interaction with putative environmental toxins. This motivated us to describe a tagging approach for an extensive but not exhaustive list of 55 drug metabolizing enzyme genes. We use these data to illustrate the power, and some of the limitations of a haplotype tagging approach. We show that haplotype tagging is extremely efficient and works well with only a modest increase in effort through different populations. The tagging approach works much less well if the minor allele frequency is below 5%. However, it will now be possible using these tags to evaluate these genes comprehensively in PD and other neurodegenerative conditions.

Genetic variations in drug-metabolizing enzyme CYP2C9 among major ethnic groups of Pakistani population

Gene ◽  
2020 ◽  
Vol 746 ◽  
pp. 144659 ◽  
Author(s):  
Hizbullah ◽  
Sagheer Ahmed ◽  
Mah Noor Mumtaz ◽  
Zaira Zulfiqar ◽  
Sheikh Amir Hamza ◽  
...  
Keyword(s):  
Ethnic Groups ◽  
Genetic Variations ◽  
Pakistani Population ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme

The Effects of Drug Metabolizing Enzyme Inhibitors on Hepatic Efflux and Uptake Transporters

2018 ◽  
Vol 11 (2) ◽  
Author(s):  
Jonathan Cheong ◽  
Jason S. Halladay ◽  
Emile Plise ◽  
Jasleen K. Sodhi ◽  
Laurent Salphati
Keyword(s):  
Enzyme Inhibitors ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Uptake Transporters

scholarly journals The effects of the new macrolide antibiotic clarithromycin on hepatic drug- $$$metabolizing enzyme in rats

1992 ◽  
Vol 58 ◽  
pp. 331
Author(s):  
Reiji Kitashiro ◽  
Norimitsu Kurata ◽  
Shinichi Kobayashi ◽  
Yuki Nishimura ◽  
Eiji Uchida ◽  
...  
Keyword(s):  
Macrolide Antibiotic ◽  
Hepatic Drug ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme

scholarly journals An Efficient Method for the Differentiation of Human iPSC-Derived Endoderm toward Enterocytes and Hepatocytes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 812
Author(s):  
Shimeng Qiu ◽  
Yaling Li ◽  
Yuki Imakura ◽  
Shinji Mima ◽  
Tadahiro Hashita ◽  
...  
Keyword(s):  
Small Intestine ◽  
Activin A ◽  
Double Positive ◽  
Differentiation Method ◽  
Drug Metabolizing Enzyme ◽  
Human Ipscs ◽  
Novel Method ◽  
Induced Pluripotent ◽  
Metabolizing Enzyme ◽  
Human Ipsc

The endoderm, differentiated from human induced pluripotent stem cells (iPSCs), can differentiate into the small intestine and liver, which are vital for drug absorption and metabolism. The development of human iPSC-derived enterocytes (HiEnts) and hepatocytes (HiHeps) has been reported. However, pharmacokinetic function-deficiency of these cells remains to be elucidated. Here, we aimed to develop an efficient differentiation method to induce endoderm formation from human iPSCs. Cells treated with activin A for 168 h expressed higher levels of endodermal genes than those treated for 72 h. Using activin A (days 0–7), CHIR99021 and PI−103 (days 0–2), and FGF2 (days 3–7), the hiPSC-derived endoderm (HiEnd) showed 97.97% CD−117 and CD−184 double-positive cells. Moreover, HiEnts derived from the human iPSC line Windy had similar or higher expression of small intestine-specific genes than adult human small intestine. Activities of the drug transporter P-glycoprotein and drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5 were confirmed. Additionally, Windy-derived HiHeps expressed higher levels of hepatocyte- and pharmacokinetics-related genes and proteins and showed higher CYP3A4/5 activity than those derived through the conventional differentiation method. Thus, using this novel method, the differentiated HiEnts and HiHeps with pharmacokinetic functions could be used for drug development.

scholarly journals Generation of tetracycline-controllable CYP3A4-expressing Caco-2 cells by the piggyBac transposon system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Moe Ichikawa ◽  
Hiroki Akamine ◽  
Michika Murata ◽  
Sumito Ito ◽  
Kazuo Takayama ◽  
...  
Keyword(s):  
Small Intestine ◽  
Drug Absorption ◽  
Cell Model ◽  
Negative Effects ◽  
Piggybac Transposon ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cyp3a4 Expression

AbstractCaco-2 cells are widely used as an in vitro intestinal epithelial cell model because they can form a monolayer and predict drug absorption with high accuracy. However, Caco-2 cells hardly express cytochrome P450 (CYP), a drug-metabolizing enzyme. It is known that CYP3A4 is the dominant drug-metabolizing enzyme in human small intestine. In this study, we generated CYP3A4-expressing Caco-2 (CYP3A4-Caco-2) cells and attempted to establish a model that can simultaneously evaluate drug absorption and metabolism. CYP3A4-Caco-2 cells were generated by piggyBac transposon vectors. A tetracycline-controllable CYP3A4 expression cassette (tet-on system) was stably transduced into Caco-2 cells, thus regulating the levels of CYP3A4 expression depending on the doxycycline concentration. The CYP3A4 expression levels in CYP3A4-Caco-2 cells cultured in the presence of doxycycline were similar to or higher than those of adult small intestine. The CYP3A4-Caco-2 cells had enough ability to metabolize midazolam, a substrate of CYP3A4. CYP3A4 overexpression had no negative effects on cell proliferation, barrier function, and P-glycoprotein activity in Caco-2 cells. Thus, we succeeded in establishing Caco-2 cells with CYP3A4 metabolizing activity comparable to in vivo human intestinal tissue. This cell line would be useful in pharmaceutical studies as a model that can simultaneously evaluate drug absorption and metabolism.

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