scholarly journals Effects of Genetic Polymorphisms of Cathepsin A on Metabolism of Tenofovir Alafenamide

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2026
Author(s):  
Soichiro Ito ◽  
Takeshi Hirota ◽  
Miyu Yanai ◽  
Mai Muto ◽  
Eri Watanabe ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Single Strand Conformation Polymorphism ◽  
Expression Level ◽  
Exon 2 ◽  
Drug Metabolizing Enzyme ◽  
293 Cells ◽  
Immunodeficiency Virus ◽  
Tenofovir Alafenamide ◽  
Metabolizing Enzyme ◽  
Japanese Subjects

Cathepsin A (CatA) is important as a drug-metabolizing enzyme responsible for the activation of prodrugs, such as the anti-human immunodeficiency virus drug Tenofovir Alafenamide (TAF). The present study was undertaken to clarify the presence of polymorphisms of the CatA gene in healthy Japanese subjects and the influence of gene polymorphism on the expression level of CatA protein and the drug-metabolizing activity. Single-strand conformation polymorphism method was used to analyze genetic polymorphisms in healthy Japanese subjects. Nine genetic polymorphisms were identified in the CatA gene. The polymorphism (85_87CTG>-) in exon 2 was a mutation causing a deletion of leucine, resulting in the change of the leucine 9-repeat (Leu9) to 8-repeat (Leu8) in the signal peptide region of CatA protein. The effect of Leu8 on the expression level of CatA protein was evaluated in Flp-In-293 cells with a stably expressed CatA, resulting in the expression of CatA protein being significantly elevated in variant 2 with Leu8 compared with Leu9. Higher concentrations of tenofovir alanine (TFV-Ala), a metabolite of TAF, were observed in the Leu8-expressing cells than in the Leu9-expressing cells using LC/MS/MS. Our findings suggest that the drug metabolic activity of CatA is altered by the genetic polymorphism.

Genetic Polymorphisms of CYP2D6: Prevalence in Healthy Kurds

2020 ◽  
Vol 17 (1) ◽  
pp. 40-47
Author(s):  
Muslih Abdulkarim Ibrahim ◽  
Zalina Zahari ◽  
Nurfadhlina Musa ◽  
Khoo Boon Yin
Keyword(s):  
Gene Duplication ◽  
Genetic Polymorphisms ◽  
Cyp2d6 Genotype ◽  
Genotype Frequencies ◽  
Drug Metabolizing Enzyme ◽  
Clinical Consequences ◽  
Polymerase Chain ◽  
Variant Alleles ◽  
Metabolizing Enzyme ◽  
Cyp2d6 Polymorphisms

Background: Identifying the genetic polymorphisms of drug metabolizing enzyme CYP2D6 is useful in pharmacogenomics. Unfortunately, until today, the prevalence of the CYP2D6 polymorphisms among Kurds is scarce. Objective: In this study, we explored the CYP2D6 polymorphisms among Kurds. Methods: Four hundred and fifty-nine unrelated healthy Kurds were recruited for the study. DNA was extracted from whole blood and was then used for genotyping CYP2D6*3, *4, *5, *6, *9, *10, *17, *114 and gene duplication using the nested allelespecific multiplex Polymerase Chain Reaction (PCR). Conclusion: The data add to our knowledge of CYP2D6 alleles, the genotypes and the distributions of predicted phenotypes in Kurds. Majority of the observed variant alleles confer no function and gene duplication. CYP2D6 polymorphisms were found to be very heterogeneous in relation to genotype frequencies. Further study in relation to the evaluation of drug therapy adjustment based on CYP2D6 genotype may help to understand the clinical consequences of CYP2D6 polymorphisms.

Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population

Xenobiotica ◽  
2015 ◽  
Vol 46 (8) ◽  
pp. 709-714 ◽  
Author(s):  
Tianbo Jin ◽  
Xiaojie Xun ◽  
Shuli Du ◽  
Tingting Geng ◽  
Hong Wang ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Drug Metabolizing Enzyme ◽  
Uyghur Population ◽  
Metabolizing Enzyme

scholarly journals Genetic polymorphisms of the drug-metabolizing enzyme CYP2J2 in a Tibetan population

Medicine ◽  
2018 ◽  
Vol 97 (40) ◽  
pp. e12579 ◽  
Author(s):  
Peilong Cao ◽  
Qian Zhao ◽  
Yuan Shao ◽  
Hua Yang ◽  
Tianbo Jin ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Tibetan Population ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme

Genetic polymorphisms of the drug-metabolizing enzyme cytochrome P450 3A5 in a Uyghur Chinese population

Xenobiotica ◽  
2016 ◽  
Vol 46 (9) ◽  
pp. 850-856 ◽  
Author(s):  
Zhengshuai Chen ◽  
Jingjie Li ◽  
Peng Chen ◽  
Fengjiao Wang ◽  
Ning Zhang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Genetic Polymorphisms ◽  
Chinese Population ◽  
Drug Metabolizing Enzyme ◽  
Cytochrome P450 3A5 ◽  
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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