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Exploring Cytochromes P450: Drug Metabolism, Endogenous Metabolism, and Human Health
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Exploring Cytochromes P450: Drug Metabolism, Endogenous Metabolism, and Human Health

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

Deadline for manuscript submissions: closed (10 May 2024) | Viewed by 1596

Special Issue Editors

Dr. Ewa Bromek

E-Mail Website
Guest Editor
Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
Interests: cytochrome P450; antidepressants; drug metabolism; brain metabolism
Prof. Dr. Władysława Anna Daniel

E-Mail Website
Guest Editor
Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
Interests: pharmacokinetics; pharmacology; biochemistry
Special Issues, Collections and Topics in MDPI journals
Dr. Wojciech Kuban

E-Mail Website
Guest Editor
Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
Interests: cytochrome P450; drug interaction; molecular dynamics; neurotoxicity; novel drug discover; gene therapy; neurodegenerative diseases

Special Issue Information

Dear Colleagues,

Cytochrome P450 (CYP) represents an enzyme group that is characterized by a hemeprotein structure and pivotal for metabolizing both endogenous compounds such as steroids, arachidonic acid, and neurotransmitters and xenobiotics such as drugs and toxins. Consequently, these enzymes hold substantial physiological, pharmacological, and toxicological significance. Nearly 80% of oxidative metabolism and approximately 50% of the comprehensive elimination of commonly prescribed clinical drugs can be attributed to members of the CYP 1–3 subfamily.

The regulation of CYPs is a multifaceted process, unfolding across multiple levels. Critical physiological modulators of these enzymes include hormones, cytokines, and neurotransmitters. Moreover, numerous nuclear factors are engaged in the transcriptional control of CYP genes. Various pharmaceutical agents and drugs of abuse have the capacity to influence CYP metabolism via different mechanisms. In addition, some CYP enzymes are genetically polymorphic or change with age, which affects their ability to metabolize both endogenous and exogenous substrates.

Changes in cytochrome P450 due to the abovementioned characteristics can lead to variations in how an individual patient responds to medications or environmental pollutions. This aspect is of the utmost importance in the field of medical treatment, where it can have a substantial influence on both the efficacy and safety of therapeutic interventions. Thus, personalized pharmacotherapy is highly recommended.

Dr. Ewa Bromek
Prof. Dr. Władysława Anna Daniel
Dr. Wojciech Kuban
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. 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
  • endogenous substrate metabolism
  • liver metabolism
  • brain metabolism

Published Papers (2 papers)

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Research

16 pages, 2937 KiB  
Article
On the Possible Effect of Phytic Acid (Myo-Inositol Hexaphosphoric Acid, IP6) on Cytochromes P450 and Systems of Xenobiotic Metabolism in Different Hepatic Models
by Veronika Frybortova, Stefan Satka, Lenka Jourova, Iveta Zapletalova, Martin Srejber, Philippe Briolotti, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin, Pavel Anzenbacher, Michal Otyepka and Eva Anzenbacherova
Int. J. Mol. Sci. 2024, 25(7), 3610; https://doi.org/10.3390/ijms25073610 - 23 Mar 2024
Viewed by 534
Abstract
As compounds of natural origin enter human body, it is necessary to investigate their possible interactions with the metabolism of drugs and xenobiotics in general, namely with the cytochrome P450 (CYP) system. Phytic acid (myo-inositol hexaphosphoric acid, IP6) is mainly present in plants [...] Read more.
As compounds of natural origin enter human body, it is necessary to investigate their possible interactions with the metabolism of drugs and xenobiotics in general, namely with the cytochrome P450 (CYP) system. Phytic acid (myo-inositol hexaphosphoric acid, IP6) is mainly present in plants but is also an endogenous compound present in mammalian cells and tissues. It has been shown to exhibit protective effect in many pathological conditions. For this paper, its interaction with CYPs was studied using human liver microsomes, primary human hepatocytes, the HepG2 cell line, and molecular docking. Docking experiments and absorption spectra demonstrated the weak ability of IP6 to interact in the heme active site of CYP1A. Molecular docking suggested that IP6 preferentially binds to the protein surface, whereas binding to the active site of CYP1A2 was found to be less probable. Subsequently, we investigated the ability of IP6 to modulate the metabolism of xenobiotics for both the mRNA expression and enzymatic activity of CYP1A enzymes. Our findings revealed that IP6 can slightly modulate the mRNA levels and enzyme activity of CYP1A. However, thanks to the relatively weak interactions of IP6 with CYPs, the chances of the mechanisms of clinically important drug–drug interactions involving IP6 are low. Full article
(This article belongs to the Special Issue Exploring Cytochromes P450: Drug Metabolism, Endogenous Metabolism, and Human Health)
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15 pages, 2484 KiB  
Article
Molecular Mechanisms of the Regulation of Liver Cytochrome P450 by Brain NMDA Receptors and via the Neuroendocrine Pathway—A Significance for New Psychotropic Therapies
by Renata Pukło, Ewa Bromek, Anna Haduch, Agnieszka Basińska-Ziobroń, Wojciech Kuban and Władysława A. Daniel
Int. J. Mol. Sci. 2023, 24(23), 16840; https://doi.org/10.3390/ijms242316840 - 28 Nov 2023
Viewed by 760
Abstract
Recent investigations have highlighted the potential utility of the selective antagonist of the NMDA receptor GluN2B subunit for addressing major depressive disorders. Our previous study showed that the systemic administration of the antagonist of the GluN2B subunit of the NMDA receptor, the compound [...] Read more.
Recent investigations have highlighted the potential utility of the selective antagonist of the NMDA receptor GluN2B subunit for addressing major depressive disorders. Our previous study showed that the systemic administration of the antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, affected liver cytochrome P450 expression and activity. To discern between the central and peripheral mechanisms of enzyme regulation, our current study aimed to explore whether the intracerebral administration of CP-101,606 could impact cytochrome P450. The injection of CP-101,606 to brain lateral ventricles (6, 15, or 30 µg/brain) exerted dose-dependent effects on liver cytochrome P450 enzymes and hypothalamic or pituitary hormones. The lowest dose led to an increase in the activity, protein, and mRNA level of CYP2C11 compared to the control. The activities of CYP2A, CYP2B, CYP2C11, CYP2C6, CYP2D, and protein levels of CYP2B, CYP2C11 were enhanced compared to the highest dose. Moreover, CP-101,606 increased the CYP1A protein level coupled with elevated CYP1A1 and CYP1A2 mRNA levels, but not activity. The antagonist decreased the pituitary somatostatin level and increased the serum growth hormone concentration after the lowest dose, while independently decreasing the serum corticosterone concentration of the dose. The findings presented here unveil a novel physiological regulatory mechanism whereby the brain glutamatergic system, via the NMDA receptor, influences liver cytochrome P450. This regulatory process appears to involve the endocrine system. These results may have practical applications in predicting alterations in cytochrome P450 activity and endogenous metabolism, and potential metabolic drug–drug interactions elicited by drugs that cross the blood–brain barrier and affect NMDA receptors. Full article
(This article belongs to the Special Issue Exploring Cytochromes P450: Drug Metabolism, Endogenous Metabolism, and Human Health)
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