The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family

Human Cytochrome P450 (CYP) enzymes constitute a superfamily of membrane-bound hemoproteins that are responsible for the metabolism of a wide variety of clinically, physiologically, and toxicologically important compounds. These heme-thiolate monooxygenases play a pivotal role in the detoxification of xenobiotics, participating in the metabolism of many structurally diverge compounds. This short-review is intended to provide a summary on the major roles of CYPs in Phase I xenobiotic metabolism. The manuscript is focused on eight main topics that include the most relevant aspects of past and current CYP research. Initially, (I) a general overview of the main aspects of absorption, distribution, metabolism, and excretion (ADME) of xenobiotics are presented. This is followed by (II) a background overview on major achievements in the past of the CYP research field. (III) Classification and nomenclature of CYPs is briefly reviewed, followed by (IV) a summary description on CYP’s location and function in mammals. Subsequently, (V) the physiological relevance of CYP as the cornerstone of Phase I xenobiotic metabolism is highlighted, followed by (VI) reviewing both genetic determinants and (VI) nongenetic factors in CYP function and activity. The last topic of the review (VIII) is focused on the current challenges of the CYP research field.

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Metabolism of the Marine Phycotoxin PTX-2 and Its Effects on Hepatic Xenobiotic Metabolism: Activation of Nuclear Receptors and Modulation of the Phase I Cytochrome P450

Toxins ◽

10.3390/toxins9070212 ◽

2017 ◽

Vol 9 (7) ◽

pp. 212 ◽

Cited By ~ 3

Author(s):

Jimmy Alarcan ◽

Estelle Dubreil ◽

Antoine Huguet ◽

Dominique Hurtaud-Pessel ◽

Stefanie Hessel-Pras ◽

...

Keyword(s):

Cytochrome P450 ◽

Phase I ◽

Nuclear Receptors ◽

Xenobiotic Metabolism

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Polymer models of the organization of chromosomes in the nucleus of cells

Modern Physics Letters B ◽

10.1142/s0217984915300033 ◽

2015 ◽

Vol 29 (09) ◽

pp. 1530003 ◽

Cited By ~ 7

Author(s):

Andrea Maria Chiariello ◽

Simona Bianco ◽

Andrea Piccolo ◽

Carlo Annunziatella ◽

Mariano Barbieri ◽

...

Keyword(s):

New Technologies ◽

Life Sciences ◽

Cell Types ◽

Short Review ◽

Research Field ◽

Polymer Physics ◽

Important Research ◽

Polymer Models ◽

Open Issue ◽

And Function

Understanding the mechanisms that control the organization of chromosomes in the space of the nucleus of cells, and its contribution to gene regulation, is a key open issue in molecular biology. New technologies have shown that chromosomes have a complex 3D organization, which dynamically changes across organisms and cell types. To understand such complex behaviors, quantitative models from polymer physics have been developed, to find the principles of chromosome folding, their origin and function. Here, we provide a short review of recent progress in such an important research field where Physical and Life Sciences meet.

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Toxicokinetics of lefetamine and derived diphenylethylamine designer drugs—Contribution of human cytochrome P450 isozymes to their main phase I metabolic steps

Toxicology Letters ◽

10.1016/j.toxlet.2015.08.012 ◽

2015 ◽

Vol 238 (3) ◽

pp. 39-44 ◽

Cited By ~ 12

Author(s):

Carina S.D. Wink ◽

Golo M.J. Meyer ◽

Markus R. Meyer ◽

Hans H. Maurer

Keyword(s):

Cytochrome P450 ◽

Phase I ◽

Main Phase ◽

Designer Drugs ◽

Human Cytochrome ◽

P450 Isozymes ◽

Cytochrome P450 Isozymes

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Electron transfer in the complex of membrane-bound human cytochrome P450 3A4 with the flavin domain of P450BM-3: The effect of oligomerization of the heme protein and intermittent modulation of the spin equilibrium

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2009.12.008 ◽

2010 ◽

Vol 1797 (3) ◽

pp. 378-390 ◽

Cited By ~ 39

Author(s):

Dmitri R. Davydov ◽

Elena V. Sineva ◽

Srinivas Sistla ◽

Nadezhda Y. Davydova ◽

Daniel J. Frank ◽

...

Keyword(s):

Electron Transfer ◽

Cytochrome P450 ◽

Heme Protein ◽

Cytochrome P450 3A4 ◽

Human Cytochrome ◽

Flavin Domain ◽

Membrane Bound

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Lipidomics of the brain, retina, and biofluids: from the biological landscape to potential clinical application in schizophrenia

Translational Psychiatry ◽

10.1038/s41398-020-01080-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Chuanjun Zhuo ◽

Weihong Hou ◽

Hongjun Tian ◽

Lina Wang ◽

Ranli Li

Keyword(s):

Animal Studies ◽

Biological Function ◽

Normal Structure ◽

Research Field ◽

Future Directions ◽

Brain Functioning ◽

Lipid Species ◽

Membrane Bound ◽

And Function ◽

The Brain

Abstract Schizophrenia is a serious neuropsychiatric disorder, yet a clear pathophysiology has not been identified. To date, neither the objective biomarkers for diagnosis nor specific medications for the treatment of schizophrenia are clinically satisfactory. It is well accepted that lipids are essential to maintain the normal structure and function of neurons in the brain and that abnormalities in neuronal lipids are associated with abnormal neurodevelopment in schizophrenia. However, lipids and lipid-like molecules have been largely unexplored in contrast to proteins and their genes in schizophrenia. Compared with the gene- and protein-centric approaches, lipidomics is a recently emerged and rapidly evolving research field with particular importance for the study of neuropsychiatric disorders such as schizophrenia, in which even subtle aberrant alterations in the lipid composition and concentration of the neurons may disrupt brain functioning. In this review, we aimed to highlight the lipidomics of the brain, retina, and biofluids in both human and animal studies, discuss aberrant lipid alterations in correlation with schizophrenia, and propose future directions from the biological landscape towards potential clinical applications in schizophrenia. Recent studies are in support of the concept that aberrations in some lipid species [e.g. phospholipids, polyunsaturated fatty acids (PUFAs)] lead to structural alterations and, in turn, impairments in the biological function of membrane-bound proteins, the disruption of cell signaling molecule accessibility, and the dysfunction of neurotransmitter systems. In addition, abnormal lipidome alterations in biofluids are linked to schizophrenia, and thus they hold promise in the discovery of biomarkers for the diagnosis of schizophrenia.

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Endogenous insertion of non-native metalloporphyrins into human membrane cytochrome P450 enzymes

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.005417 ◽

2018 ◽

Vol 293 (43) ◽

pp. 16623-16634 ◽

Cited By ~ 2

Author(s):

Rahul Yadav ◽

Emily E. Scott

Keyword(s):

Cytochrome P450 ◽

Solution Nmr ◽

Uptake System ◽

Structural Studies ◽

Cytochrome P450 Enzymes ◽

Prosthetic Group ◽

Human Cytochrome ◽

Membrane Bound ◽

Folded Proteins ◽

Iron Protoporphyrin

Human cytochrome P450 enzymes are membrane-bound heme-containing monooxygenases. As is the case for many heme-containing enzymes, substitution of the metal in the center of the heme can be useful for mechanistic and structural studies of P450 enzymes. For many heme proteins, the iron protoporphyrin prosthetic group can be extracted and replaced with protoporphyrin containing another metal, but human membrane P450 enzymes are not stable enough for this approach. The method reported herein was developed to endogenously produce human membrane P450 proteins with a nonnative metal in the heme. This approach involved coexpression of the P450 of interest, a heme uptake system, and a chaperone in Escherichia coli growing in iron-depleted minimal medium supplemented with the desired trans-metallated protoporphyrin. Using the steroidogenic P450 enzymes CYP17A1 and CYP21A2 and the drug-metabolizing CYP3A4, we demonstrate that this approach can be used with several human P450 enzymes and several different metals, resulting in fully folded proteins appropriate for mechanistic, functional, and structural studies including solution NMR.

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Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2

Physical Chemistry Chemical Physics ◽

10.1039/c6cp03692a ◽

2016 ◽

Vol 18 (44) ◽

pp. 30344-30356 ◽

Cited By ~ 16

Author(s):

Petr Jeřábek ◽

Jan Florián ◽

Václav Martínek

Keyword(s):

Molecular Dynamics ◽

Aqueous Solution ◽

Cytochrome P450 ◽

Molecular Dynamics Simulations ◽

Coarse Grained ◽

Cytochrome P450 1A2 ◽

Structure And Dynamics ◽

Human Cytochrome ◽

Membrane Bound ◽

Dynamics Simulations

The structure and dynamics of the membrane-bound full-length human cytochrome P450 1A2 (CYP1A2) in aqueous solution determined by coarse-grained and all-atom molecular dynamics simulations.

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