The correlation between the expression of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts

Wang, Jianhai; Li, Keqiu; Zhang, Xiaoning; Teng, Dahong; Ju, Mingyan; Jing, Yaqing; Zhao, Yijiao; Li, Guang

doi:10.1038/s41598-017-02698-w

Cited by 8 publications

(6 citation statements)

References 43 publications

(44 reference statements)

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“…Among all the covariates we studied, pre-operation serum creatinine concentration of recipients in the CP was the only variable that showed statistical significance. In keeping with our findings, serum creatinine was previously shown to be relevant in tacrolimus metabolism (Wang et al, 2017), whereas the other baseline characteristics we studied have been reported to have no effect. Interestingly, serum creatinine only influenced tacrolimus metabolism during CP, showing that, to a certain extent, the major factors affecting tacrolimus metabolism were genetic.…”

Section: Discussionsupporting

confidence: 90%

Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function

Liu

Zhang

et al. 2019

Front. Genet.

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After liver transplantation, the liver function of a patient is gradually restored over a period of time that can be divided into a convalescence period (CP) and a stabilizing period (SP). The plasma concentration of tacrolimus, an immunosuppressant commonly used to prevent organ rejection, varies as a result of variations in its metabolism. The effects of genetic and clinical factors on the plasma concentration of tacrolimus appear to differ in the CP and SP. To establish a model explaining the variation in tacrolimus trough concentration between individuals in the CP and SP, we conducted a retrospective, single-center, discovery study of 115 pairs of patients (115 donors and 115 matched recipients) who had undergone liver transplantation. Donors and recipients were genotyped by a genome-wide association study (GWAS) using an exome chip. Novel exons were identified that influenced tacrolimus trough concentrations and were verified with bootstrap analysis. In donors, two single-nucleotide polymorphisms showed an effect on the CP (rs1927321, rs1057192) and four showed an effect on the SP (rs776746, rs2667662, rs7980521, rs4903096); in recipients, two single-nucleotide polymorphisms showed an effect in the SP (rs7828796, rs776746). Genetic factors played a crucial role in tacrolimus metabolism, accounting for 44.8% in the SP, which was higher than previously reported. In addition, we found that CYP3A5, which is known to affect the metabolism of tacrolimus, only influenced tacrolimus pharmacokinetics in the SP.

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Section: Discussionsupporting

confidence: 90%

Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function

Liu

Zhang

et al. 2019

Front. Genet.

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“…However, CYP4F2 metabolizes the ester prodrug of gemcitabine and the antiparasitic pafuramidine [57]. In addition, CYP4A11 exhibited metabolism of the immune suppressant tacrolimus to an inactive form [58]. Although the turnover rates were low compared to those of CYP3A4, CYP4F11 exhibited catalytic activity towards commonly used drugs such as erythromycin, benzphetamine, and chlorpromazine [36,37,59].…”

Section: Role Of the Cyp4 Family In The Metabolism Of Drugsmentioning

confidence: 99%

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

Jarrar

Lee

2019

IJMS

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Enzymes in the cytochrome P450 4 (CYP4) family are involved in the metabolism of fatty acids, xenobiotics, therapeutic drugs, and signaling molecules, including eicosanoids, leukotrienes, and prostanoids. As CYP4 enzymes play a role in the maintenance of fatty acids and fatty-acid-derived bioactive molecules within a normal range, they have been implicated in various biological functions, including inflammation, skin barrier, eye function, cardiovascular health, and cancer. Numerous studies have indicated that genetic variants of CYP4 genes cause inter-individual variations in metabolism and disease susceptibility. Genetic variants of CYP4A11, 4F2 genes are associated with cardiovascular diseases. Mutations of CYP4B1, CYP4Z1, and other CYP4 genes that generate 20-HETE are a potential risk for cancer. CYP4V2 gene variants are associated with ocular disease, while those of CYP4F22 are linked to skin disease and CYP4F3B is associated with the inflammatory response. The present study comprehensively collected research to provide an updated view of the molecular functionality of CYP4 genes and their associations with human diseases. Functional analysis of CYP4 genes with clinical implications is necessary to understand inter-individual variations in disease susceptibility and for the development of alternative treatment strategies.

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“…CYP450 is an essential metabolic enzyme present in most organisms, of which the highest levels are found in the endoplasmic reticulum of liver cells, which helps in the biotransformation of most exogenous substances . Studies have found that CYP450 could catalyze AA to 20-HETE and EETS for lipid metabolism, inflammatory reaction, and oxidative stress. − As the metabolites catalyzed by COXs from AA, PGs are the key regulators of the renal vasomotor tone. Therefore, abnormal generation of PGs could cause anoxia and reduced renal blood flow, which may stimulate renal injury, inflammation, and fibrotic injury.…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Combined with Metabolomics Approach to Investigate the Toxicity Mechanism of Paclobutrazol

Yue

Liu

et al. 2022

Chem. Res. Toxicol.

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Paclobutrazol (PBZ) is a commonly used plant growth regulator (PGR) with good antibacterial activity. It has widespread applications in agricultural production. However, there is limited research reported on the potential risks of human health resulting from PBZ residues. In this study, using Sprague-Dawley rats, we carried out a systematic study on the hepatotoxicity and nephrotoxicity of PBZ in different doses (0.2, 0.5, and 1.0 g/kg). The metabolic profiles and network pharmacology were combined to construct a PBZ−endogenous substances−gene−hepatorenal diseases network to elucidate the underlying mechanism of PBZ's hepatorenal toxicity. At first, metabolomics analysis was done to investigate the metabolites and the related metabolic pathways associated with PBZ. Secondly, the network pharmacology approach was used in further exploration of the toxic targets. Additionally, molecular docking was carried out to investigate the interactions between PBZ and potential targets. The results indicated that PBZ showed obvious toxicity towards the liver and kidney of rats. The metabolomics analysis showed that PBZ mainly affected 4 metabolic pathways, including tryptophan metabolism, arachidonic acid metabolism, linoleic acid metabolism, and purine metabolism. Network pharmacology and molecular docking revealed that CYP1A2, CYP2A6, CYP2E1, MAOA, PLA2G2A, PTGS1, and XDH were critical targets for PBZ hepatorenal toxicity. This preliminary study revealed PBZ's hepatorenal toxicity and provided a theoretical basis for the rational and safe use of PBZ. Furthermore, it provided possible intervention targets for further research on how to avoid or reduce the damage caused by pesticides to the human body.

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The correlation between the expression of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts

Cited by 8 publications

References 43 publications

Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function

Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

Network Pharmacology Combined with Metabolomics Approach to Investigate the Toxicity Mechanism of Paclobutrazol

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