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Biomolecules
Special Issues
Novel Insights into Cytochrome P450 Enzymes in Drug Metabolism
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Novel Insights into Cytochrome P450 Enzymes in Drug Metabolism

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: 30 June 2024 | Viewed by 3540

Special Issue Editors

Dr. Donglu Zhang

E-Mail Website
Guest Editor
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Interests: drug discovery; drug clearance pathways; enzyme inhibitors; P450 enzymes; high-resolution mass spectrometry; drug metabolites; site of metabolism; machine learning
Dr. Lionel Cheruzel

E-Mail Website
Guest Editor
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Interests: drug discovery; drug clearance pathways; enzyme inhibitors; P450 enzymes; high-resolution mass spectrometry; drug metabolites; site of metabolism; machine learning

Special Issue Information

Dear Colleagues,

As you are all well aware, cytochrome P450 enzymes play a unique and crucial role in metabolizing most drugs. While great advances have been made in understanding their role, function and mechanism, these drug-metabolizing enzymes continue to captivate scientists because of their ability to carry out unique biotransformations; their different levels of expression, concentration and activity in various organs; and the fact that they are major targets of drug–drug interaction. We would like to invite you to submit reviews or original manuscripts to this Special Issue that describe recent findings and novel insights into P450 contribution to drug metabolism, from the perspectives of both industry and academia.

We would like to thank you in advance for your consideration and we look forward to your contribution to this exciting Special Issue.

Dr. Donglu Zhang
Dr. Lionel Cheruzel
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 submissions that pass pre-check are 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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • P450 enzymes
  • oxidative metabolism
  • drug–drug interactions
  • exhepatic P450
  • bioactivation

Published Papers (3 papers)

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Research

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17 pages, 2702 KiB  
Article
Exploring Novel Variants of the Cytochrome P450 Reductase Gene (POR) from the Genome Aggregation Database by Integrating Bioinformatic Tools and Functional Assays
by Maria Natalia Rojas Velazquez, Søren Therkelsen and Amit V. Pandey
Biomolecules 2023, 13(12), 1728; https://doi.org/10.3390/biom13121728 - 30 Nov 2023
Viewed by 869
Abstract
Cytochrome P450 oxidoreductase (POR) is an essential redox partner for steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR lead to metabolic disorders, including congenital adrenal hyperplasia, and affect the metabolism of steroids, drugs, and xenobiotics. In this study, [...] Read more.
Cytochrome P450 oxidoreductase (POR) is an essential redox partner for steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR lead to metabolic disorders, including congenital adrenal hyperplasia, and affect the metabolism of steroids, drugs, and xenobiotics. In this study, we examined approximately 450 missense variants of the POR gene listed in the Genome Aggregation Database (gnomAD) using eleven different in silico prediction tools. We found that 64 novel variants were consistently predicted to be disease-causing by most tools. To validate our findings, we conducted a population analysis and selected two variations in POR for further investigation. The human POR wild type and the R268W and L577P variants were expressed in bacteria and subjected to enzyme kinetic assays using a model substrate. We also examined the activities of several cytochrome P450 proteins in the presence of POR (WT or variants) by combining P450 and reductase proteins in liposomes. We observed a decrease in enzymatic activities (ranging from 35% to 85%) of key drug-metabolizing enzymes, supported by POR variants R288W and L577P compared to WT-POR. These results validate our approach of curating a vast amount of data from genome projects and provide an updated and reliable reference for diagnosing POR deficiency. Full article
(This article belongs to the Special Issue Novel Insights into Cytochrome P450 Enzymes in Drug Metabolism)
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Review

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22 pages, 2432 KiB  
Review
The Impact of Inorganic Systems and Photoactive Metal Compounds on Cytochrome P450 Enzymes and Metabolism: From Induction to Inhibition
by Dmytro Havrylyuk, David K. Heidary and Edith C. Glazer
Biomolecules 2024, 14(4), 441; https://doi.org/10.3390/biom14040441 - 04 Apr 2024
Viewed by 550
Abstract
While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP [...] Read more.
While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP expression, modify enzyme interactions with reductase partners, and serve as direct inhibitors. This commonly overlooked topic is reviewed here, with an emphasis on understanding the structural and physiochemical basis for these interactions. Intriguingly, while both organometallic and coordination compounds can act as potent CYP inhibitors, there is little evidence for the metabolism of inorganic compounds by CYPs, suggesting a potential alternative approach to evading issues associated with rapid modification and elimination of medically useful compounds. Full article
(This article belongs to the Special Issue Novel Insights into Cytochrome P450 Enzymes in Drug Metabolism)
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26 pages, 3188 KiB  
Review
A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment
by Jonghwa Lee, Jessica L. Beers, Raeanne M. Geffert and Klarissa D. Jackson
Biomolecules 2024, 14(1), 99; https://doi.org/10.3390/biom14010099 - 12 Jan 2024
Cited by 1 | Viewed by 1796
Abstract
Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential [...] Read more.
Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential starts with in vitro experiments to determine kinetic parameters and identify risks associated with the use of comedication that can inform future clinical studies. The diverse range of experimental models and techniques has significantly contributed to the examination of potential DDIs. Cytochrome P450 (CYP) enzymes are responsible for the biotransformation of many drugs on the market, making them frequently implicated in drug metabolism and DDIs. Consequently, there has been a growing focus on the assessment of DDI risk for CYPs. This review article provides mechanistic insights underlying CYP inhibition/induction and an overview of the in vitro assessment of CYP-mediated DDIs. Full article
(This article belongs to the Special Issue Novel Insights into Cytochrome P450 Enzymes in Drug Metabolism)
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