Dataset Information

Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C972-75 in the Chinese Han population.

ABSTRACT: Cytochrome 2C9 (CYP2C9), one of the most important drug metabolic enzymes in the human hepatic P450 superfamily, is required for the metabolism of 15% of clinical drugs. Similar to other CYP2C family members, CYP2C9 gene has a high genetic polymorphism which can cause significant racial and inter-individual differences in drug metabolic activity. To better understand the genetic distribution pattern of CYP2C9 in the Chinese Han population, 931 individuals were recruited and used for the genotyping in this study. As a result, seven synonymous and 14 non-synonymous variations were identified, of which 4 missense variants were designated as new alleles CYP2C9*72, *73, *74 and *75, resulting in the amino acid substitutions of A149V, R150C, Q214H and N418T, respectively. When expressed in insect cell microsomes, all four variants exhibited comparable protein expression levels to that of the wild-type CYP2C9 enzyme. However, drug metabolic activity analysis revealed that these variants exhibited significantly decreased catalytic activities toward three CYP2C9 specific probe drugs, as compared with that of the wild-type enzyme. These data indicate that the amino acid substitution in newly designated variants can cause reduced function of the enzyme and its clinical significance still needs further investigation in the future.

SUBMITTER: Zhao FL

PROVIDER: S-EPMC9792615 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C972-75 in the Chinese Han population.

Zhao Fang-Ling FL Zhang Qing Q Wang Shuang-Hu SH Hong Yun Y Zhou Shan S Zhou Quan Q Geng Pei-Wu PW Luo Qing-Feng QF Yang Jie-Fu JF Chen Hao H Cai Jian-Ping JP Dai Da-Peng DP

Frontiers in pharmacology 20221213

Cytochrome 2C9 (CYP2C9), one of the most important drug metabolic enzymes in the human hepatic P450 superfamily, is required for the metabolism of 15% of clinical drugs. Similar to other CYP2C family members, CYP2C9 gene has a high genetic polymorphism which can cause significant racial and inter-individual differences in drug metabolic activity. To better understand the genetic distribution pattern of CYP2C9 in the Chinese Han population, 931 individuals were recruited and used fo ...[more]

PMID: 36582532

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Project description:Psoriasis is a chronic inflammatory skin disease related to immune, whose complexity of molecular mechanisms is still not fully clear. RNA sequencing has been widely applied in various fields including biological medicine. According to the bioinformatics analysis of differential genes, biomarkers and drug targets have been discovered for the diagnosis and treatment of diseases. Besides, the pathological mechanisms of disease and functions of gene can be evaluated. In the present study, we report the application of RNA sequencing in skin tissues from psoriatic and healthy persons. By obtaining 2139 differential expressed genes (DEGs), 208 significantly differential GO terms and 44 significantly differential pathways were generated. We found that the functions of DEGs were mainly related to cell cycle, inflammatory, virus, immune response and metabolic process.The major pathways included cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, chemokine signaling pathway, cell cycle, metabolic pathways, ribosome, peroxisome, steroid biosynthesis and biosynthesis of unsaturated fatty acids. Furthermore, co-expression network was constructed to identify core genes and relations between genes. we considered genes with high values of degree and k-core difference in the co-expression network as core genes, such as IFNG, IL26, TLR3, PRKCQ, TLR4, CD274, CDK1 and IL17A. We chose CD274, an important immune checkpoint, to evaluate its regulatory mechanisms. Candidate genes related to CD274 were evaluated by the co-expression network analysis, and the relations between CD274 and candidate genes were validated in epidermal keratinocytes. Finally, IFNG and CDK1 inhibitor (indirubin) were found increasing the expression levels of CD274. In addition, indirubin was confirmed to attenuate mouse psoriasis-like skin lesion with the mechanisms related to CD274. In conclusion, this study provides us a comprehensive transcriptome analysis method on psoriasis to identify core genes and explore the important regulatory functions of genes.

Dataset Information

Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C972-75 in the Chinese Han population.

Publications

Identification and drug metabolic characterization of four new CYP2C9 variants <i>CYP2C972</i>-<i>75</i> in the Chinese Han population.

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Dataset Information

Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population.

Publications

Identification and drug metabolic characterization of four new CYP2C9 variants <i>CYP2C9*72</i>-<i>*75</i> in the Chinese Han population.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C972-75 in the Chinese Han population.

Identification and drug metabolic characterization of four new CYP2C9 variants <i>CYP2C972</i>-<i>75</i> in the Chinese Han population.