Structural insights into understudied human cytochrome P450 enzymes

Machalz, David; Pach, Szymon; Bermudez, Marcel; Bureik, Matthias; Wolber, Gerhard

doi:10.1016/j.drudis.2021.06.006

Cited by 24 publications

(15 citation statements)

References 62 publications

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“…Xenobiotic metabolism involves complex processes and a huge number of xenobioticmetabolising enzymes such as cytochromes P-450 (CYPs) as phase I enzymes and UDPglucuronosyltransferases as phase II enzymes. Such xenobiotic-metabolising enzymes have prominent roles in the metabolic fate of a wealth of endogenous and exogenous low-molecular-weight compounds [1,2]. Indeed, CYPs are major ubiquitous phase I enzymes, occurring in thousands of isoforms across bacteria, plants, fungi and animals, Toxins 2022, 14, 207 2 of 13 and play a key role in the pharmacology and toxicology of a plethora of compounds including pharmaceuticals, pesticides, food and feed additives, food components and contaminants to cite but a few.…”

Section: Introductionmentioning

confidence: 99%

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

Dorne

Cirlini

Louisse

et al. 2022

Toxins

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Cytochrome P-450 (CYP) enzymes have a key role in the metabolism of xenobiotics of food origin, and their highly polymorphic nature concurs with the diverse inter-individual variability in the toxicokinetics (TK) and toxicodynamics (TD) of food chemicals. Ochratoxin A is a well-known mycotoxin which contaminates a large variety of food and is associated with food safety concerns. It is a minor substrate of CYP2D6, although the effects of CYP2D6 polymorphisms on its metabolism may be overlooked. Insights on this aspect would provide a useful mechanistic basis for a more science-based hazard assessment, particularly to integrate inter-individual differences in CYP2D6 metabolism. This work presents a molecular modelling approach for the analysis of mechanistic features with regard to the metabolic capacity of CYP2D6 variants to oxidise a number of substrates. The outcomes highlighted that a low-frequency CYP2D6 variant (CYP2D6*110) is likely to enhance ochratoxin A oxidation with possible consequences on TK and TD. It is therefore recommended to further analyse such TK and TD consequences. Generally speaking, we propose the identification of mechanistic features and parameters that could provide a semi-quantitative means to discriminate ligands based on the likelihood to undergo transformation by CYP2D6 variants. This would support the development of a fit-for-purpose pipeline which can be extended to a tool allowing for the bulk analysis of a large number of compounds. Such a tool would ultimately include inter-phenotypic differences of polymorphic xenobiotic-metabolising enzymes in the hazard assessment and risk characterisation of food chemicals.

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Section: Introductionmentioning

confidence: 99%

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

Dorne

Cirlini

Louisse

et al. 2022

Toxins

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“…Cytochrome P450 2J2 (CYP2J2), a member of heme-thiolate proteins, is widely located in the cardiovascular system. 323,324 CYP2J2 can regulate cell progression by metabolizing endogenous polyunsaturated fatty acids. However, an excess of CYP2J2 is associated with tumorigenesis.…”

Section: Nir Fluorescent Probes For Enzymesmentioning

confidence: 99%

Activity-based NIR fluorescent probes based on the versatile hemicyanine scaffold: design strategy, biomedical applications, and outlook

et al. 2022

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“…Cytochrome P450 (CYP) enzymes are a superfamily of hemoproteins and extensively catalyze the metabolism of exogenous and endogenous compounds. CYP also exerts a crucial role in the development and progression of cancer, diabetes, heart disease, and Parkinson's disease [ 2 – 5 ]. CYP2E1 is the most abundant CYP isoform in human liver and is the main enzyme that metabolizes a number of low molecular weight compounds, such as ethanol, acetaminophen, benzene, and carbon tetrachloride, and cancer suspects like nitrosamines and azo compounds [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

CYP2E1 plays a suppressive role in hepatocellular carcinoma by regulating Wnt/Dvl2/β-catenin signaling

et al. 2022

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Objective Knowledge of the role of CYP2E1 in hepatocarcinogenesis is largely based on epidemiological and animal studies, with a primary focus on the role of CYP2E1 in metabolic activation of procarcinogens. Few studies have directly assessed the effects of CYP2E1 on HCC malignant phenotypes. Methods The expression of CYP2E1 in HCC tissues was determined by qRT-PCR, western blotting and immunohistochemistry. Overexpression of CYP2E1 in HCC cell was achieved by lentivirus transfection. The function of CYP2E1 were detected by CCK-8, wound healing, transwell assays, xenograft models and pulmonary metastasis model. TOP/FOPFlash reporter assay, western blotting, functional rescue experiments, Co-immunoprecipitation and reactive oxygen species detection were conducted to reveal the underlying mechanism of the tumor suppressive role of CYP2E1. Results CYP2E1 expression is down-regulated in HCC tissues, and this downregulation was associated with large tumor diameter, vascular invasion, poor differentiation, and shortened patient survival time. Ectopic expression of CYP2E1 inhibits the proliferation, invasion and migration and epithelial-to-mesenchymal transition of HCC cells in vitro, and inhibits tumor formation and lung metastasis in nude mice. Mechanistic investigations show that CYP2E1 overexpression significantly inhibited Wnt/β-catenin signaling activity and decreased Dvl2 expression in HCC cells. An increase in Dvl2 expression restored the malignant phenotype of HCC cells. Notably, CYP2E1 promoted the ubiquitin-mediated degradation of Dvl2 by strengthening the interaction between Dvl2 and the E3 ubiquitin ligase KLHL12 in CYP2E1-stable HCC cells. CYP2E1-induced ROS accumulation was a critical upstream event in the Wnt/β-Catenin pathway in CYP2E1-overexpressing HCC cells. Conclusions These results provide novel insight into the role of CYP2E1 in HCC and the tumor suppressor role of CYP2E1 can be attributed to its ability to manipulate Wnt/Dvl2/β-catenin pathway via inducing ROS accumulation, which provides a potential target for the prevention and treatment of HCC. Graphical Abstract

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Structural insights into understudied human cytochrome P450 enzymes

Cited by 24 publications

References 62 publications

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

A Computational Understanding of Inter-Individual Variability in CYP2D6 Activity to Investigate the Impact of Missense Mutations on Ochratoxin A Metabolism

Activity-based NIR fluorescent probes based on the versatile hemicyanine scaffold: design strategy, biomedical applications, and outlook

CYP2E1 plays a suppressive role in hepatocellular carcinoma by regulating Wnt/Dvl2/β-catenin signaling

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