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Special Issue "Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 3.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 August 2021.

Special Issue Editors

Dr. Patrick M. Dansette
E-Mail Website
Guest Editor
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 45 Rue des Saints-Pères, 75270 Paris CEDEX 06, France
Interests: drug metabolism; cytochrome P450 structure and mechanism; biological reactive intermediates; thiophene-S-oxides; arene oxides; sulfenic acid; mechanism based inhibitors; Ferrocifen; drug induced immunotoxicity.
Special Issues and Collections in MDPI journals
Prof. Arthur Roberts
E-Mail Website
Guest Editor
The University of Georgia, Department of Pharmaceutical Biomedical Sciences, Athens, 30602 GA, United States

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous two Special Issues, “Cytochromes P450: Drug Metabolism and Bioactivation” and “Cytochrome P450: Drug Metabolism and Bioactivation and Biodiversity” (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/p450).

Nearly seventy year ago, R.T. Williams and B.B. Brodie developed the concept of drug metabolism and the types of reactions and the mechanisms for the body to facilitate the excretion of a drug. Ten years later, Klingenberg and Garfinkel independently discovered the P450 protein, which was, five years later, demonstrated to be a cytochrome P450 by Omura and Sato. Later on, the prominent function of this enzyme and its role in drug metabolism and endobiotics biosynthesis were established. This resulted in a new chapter, and now more than 90,000 papers contain the concept of cytochrome P450. We are now well aware of this enzyme’s importance in clearance and potential toxicity, and, therefore, compounds do get tested for it. Moreover, this enzyme family is widely distributed in the bacterial, animal, plant, alga and viral kingdoms.

Special Issues 1 and 2 on “Cytochromes P450: Drug Metabolism and Bioactivation” were considerably successful, publishing 14 papers each. Thus, we have decided to launch a new issue with extended topics. This third Special Issue focuses on “Cytochrome P450: Drug Metabolism, Bioactivation, and Biodiversity” and will include papers on: (1) its structures, (2) types and mechanisms of reactions, (3) pharmacogenomics, (4) bioactivation reactions and biological markers, (5) mechanism-based inactivation, (6) species differences, and (7) biodiversity.

We warmly welcome submissions, including original papers and reviews, on these widely-discussed topics.

Dr. Patrick M. Dansette
Prof. Arthur Roberts
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cytochrome P450
  • drug metabolism
  • bioactivation
  • pharmacogenomics
  • reactive intermediates
  • drug induced toxicity
  • reaction mechanisms

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Published Papers (4 papers)

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Research

Open AccessArticle
Conformational Landscape of Cytochrome P450 Reductase Interactions
Int. J. Mol. Sci. 2021, 22(3), 1023; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031023 - 20 Jan 2021
Cited by 1 | Viewed by 754
Abstract
Oxidative reactions catalyzed by Cytochrome P450 enzymes (CYPs), which constitute the most relevant group of drug-metabolizing enzymes, are enabled by their redox partner Cytochrome P450 reductase (CPR). Both proteins are anchored to the membrane of the endoplasmic reticulum and the CPR undergoes a [...] Read more.
Oxidative reactions catalyzed by Cytochrome P450 enzymes (CYPs), which constitute the most relevant group of drug-metabolizing enzymes, are enabled by their redox partner Cytochrome P450 reductase (CPR). Both proteins are anchored to the membrane of the endoplasmic reticulum and the CPR undergoes a conformational change in order to interact with the respective CYP and transfer electrons. Here, we conducted over 22 microseconds of molecular dynamics (MD) simulations in combination with protein–protein docking to investigate the conformational changes necessary for the formation of the CPR–CYP complex. While some structural features of the CPR and the CPR–CYP2D6 complex that we highlighted confirmed previous observations, our simulations revealed additional mechanisms for the conformational transition of the CPR. Unbiased simulations exposed a movement of the whole protein relative to the membrane, potentially to facilitate interactions with its diverse set of redox partners. Further, we present a structural mechanism for the susceptibility of the CPR to different redox states based on the flip of a glycine residue disrupting the local interaction network that maintains inter-domain proximity. Simulations of the CPR–CYP2D6 complex pointed toward an additional interaction surface of the FAD domain and the proximal side of CYP2D6. Altogether, this study provides novel structural insight into the mechanism of CPR–CYP interactions and underlying conformational changes, improving our understanding of this complex machinery relevant for drug metabolism. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 3.0)
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Open AccessArticle
Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength
Int. J. Mol. Sci. 2021, 22(2), 852; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020852 - 16 Jan 2021
Cited by 1 | Viewed by 366
Abstract
Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug–drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition [...] Read more.
Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug–drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure–activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R1/R2 side-groups as phenyls or R1–phenyl/R2–indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl–ethyl to pyridyl–propyl, was beneficial and markedly improved Ks, IC50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (Ks and IC50 of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 3.0)
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Open AccessArticle
Dose-Dependent Effects of Resveratrol on Cisplatin-Induced Hearing Loss
Int. J. Mol. Sci. 2021, 22(1), 113; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010113 - 24 Dec 2020
Viewed by 546
Abstract
Previous preclinical studies have demonstrated the otoprotective effects of resveratrol (RV) at low doses. This study aimed to investigate the dose-dependent effects of RV in rats with cisplatin (CXP)-induced hearing loss. Sprague-Dawley rats (8-weeks old) were divided into six treatment groups (n [...] Read more.
Previous preclinical studies have demonstrated the otoprotective effects of resveratrol (RV) at low doses. This study aimed to investigate the dose-dependent effects of RV in rats with cisplatin (CXP)-induced hearing loss. Sprague-Dawley rats (8-weeks old) were divided into six treatment groups (n = 12/group) and treated as follows: control, 0.5 mg/kg RV, 50 mg/kg RV, CXP, 0.5 mg/kg RV + CXP), and 50 mg/kg RV + CXP groups. CXP (3 mg/kg) was intraperitoneally injected for 5 days. RV (0.5 or 50 mg/kg) was intraperitoneally injected for 10 days from the first day of CXP administration. Auditory brainstem response (ABR) thresholds were measured before and within 3 days at the end of the drug administration. Cochlear tissues were harvested, and the outer hair cells were examined using cochlear whole mounts. The mRNA expression of NFκB, IL6, IL1β, and CYP1A1, and protein levels of aryl hydrocarbon receptor (AhR) and cytosolic and nuclear receptor for advanced glycation endproducts (RAGE) were evaluated. The ABR threshold increased in the 50 mg/kg RV and CXP groups at 4, 8, 16, and 32 kHz. The 0.5 mg/kg RV + CXP group demonstrated decreased hearing thresholds at 4 and 32 kHz compared to the CXP group. Cochlear whole-mount analysis revealed loss of outer hair cells in the 50 mg/kg RV and CXP groups and partial prevention of these cells in the 0.5 mg/kg RV + CXP group. The mRNA expressions of NFκB, IL6, and IL1β were increased in the 50 mg/kg RV and CXP groups compared to the control group. In contrast, these levels were decreased in the 0.5 mg/kg RV + CXP group compared to the CXP group. The mRNA expression of CYP1A1 was increased in the CXP group, while it was decreased in the 0.5 mg/kg RV + CXP group compared to the control group. The protein levels of AhR and cytosolic RAGE decreased in the 0.5 mg/kg RV group. Low-dose RV had partial otoprotective effects on CXP ototoxicity. The otoprotective effects of RV may be mediated through anti-oxidative (CYP1A1 and RAGE) and anti-inflammatory (NFκB, IL6, and IL1β) responses. High-dose RV exerted an inflammatory response and did not ameliorate CXP-induced ototoxicity. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 3.0)
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Open AccessArticle
Interaction Modes of Microsomal Cytochrome P450s with Its Reductase and the Role of Substrate Binding
Int. J. Mol. Sci. 2020, 21(18), 6669; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186669 - 11 Sep 2020
Viewed by 651
Abstract
The activity of microsomal cytochromes P450 (CYP) is strictly dependent on the supply of electrons provided by NADPH cytochrome P450 oxidoreductase (CPR). The variant nature of the isoform-specific proximal interface of microsomal CYPs implies that the interacting interface between the two proteins is [...] Read more.
The activity of microsomal cytochromes P450 (CYP) is strictly dependent on the supply of electrons provided by NADPH cytochrome P450 oxidoreductase (CPR). The variant nature of the isoform-specific proximal interface of microsomal CYPs implies that the interacting interface between the two proteins is degenerated. Recently, we demonstrated that specific CPR mutations in the FMN-domain (FD) may induce a gain in activity for a specific CYP isoform. In the current report, we confirm the CYP isoform dependence of CPR’s degenerated binding by demonstrating that the effect of four of the formerly studied FD mutants are indeed exclusive of a specific CYP isoform, as verified by cytochrome c inhibition studies. Moreover, the nature of CYP’s substrate seems to have a modulating role in the CPR:CYP interaction. In silico molecular dynamics simulations of the FD evidence that mutations induces very subtle structural alterations, influencing the characteristics of residues formerly implicated in the CPR:CYP interaction or in positioning of the FMN moiety. CPR seems therefore to be able to form effective interaction complexes with its structural diverse partners via a combination of specific structural features of the FD, which are functional in a CYP isoform dependent manner, and dependent on the substrate bound. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 3.0)
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