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Cytochrome P450: Metabolism, Structure-Function, Evolution and Applications
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Cytochrome P450: Metabolism, Structure-Function, Evolution and Applications

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

Deadline for manuscript submissions: 30 October 2025 | Viewed by 5304

Special Issue Editors

Prof. Dr. Khajamohiddin Syed

E-Mail Website
Guest Editor
Department of Biochemistry and Microbiology, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa 3886, South Africa
Interests: annotation, structure-function analysis, evolution, and applications of P450s
Prof. Dr. David Lamb

E-Mail Website
Guest Editor
Institute of Life Science, Medical School, Swansea University, Swansea SA2 8PP, UK
Interests: cytochrome P450; monooxidation; redox proteins; biodiversity; evolution

Special Issue Information

Dear Colleagues,

Cytochrome P450 monooxygenases (CYPs/P450s) belong to a superfamily of heme-thiolate proteins that play a vital role in primary and secondary metabolism. P450s are ubiquitous in all domains of life, catalyzing a wide range of reactions with substrate promiscuity and stereo- and regio-specificity. Because of this, P450s have been utilized in a wide range of pharmacological, biotechnological, and environmental applications, including drug discovery and development, the production of fine chemicals, fragrances, pharmaceutical compounds, biofuels, biosensing, and bioremediation. Without being limited to a specific research category, we welcome original articles, short communications, case reports, and reviews (wet laboratory or in silico-based studies) on any topic regarding P450s.

Prof. Dr. Khajamohiddin Syed
Prof. Dr. David Lamb
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.

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Keywords

  • cytochrome P450 monooxygenase
  • metabolism
  • structure-function
  • evolution
  • applications

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Published Papers (4 papers)

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Research

24 pages, 2742 KiB  
Article
Mono-CYP CHO Model: A Recombinant Chinese Hamster Ovary Cell Platform for Investigating CYP-Specific Tamoxifen Metabolism
by Christian Schulz, Sarah Stegen, Friedrich Jung and Jan-Heiner Küpper
Int. J. Mol. Sci. 2025, 26(9), 3992; https://doi.org/10.3390/ijms26093992 - 23 Apr 2025
Viewed by 211
Abstract
The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions [...] Read more.
The metabolism of drugs and foreign substances in humans typically involves multiple enzymatic steps, particularly in phase-1 biotransformation in the liver, where various cytochrome P450 monooxygenases (CYPs) play crucial roles. This complexity can lead to a wide range of metabolites. Understanding the contributions of individual CYPs and their interactions within these intricate enzyme cascades can be challenging. We recently developed an in vitro biotransformation platform employing various Chinese Hamster Ovarian (CHO) cell clones. These clones express human cytochrome P450 oxidoreductase (CPR), and each is defined by a specific human CYP enzyme expression, thus exhibiting no detectable endogenous CYP enzyme activity (mono-CYP CHO platform). In this study, we investigated whether the mono-CYP CHO platform is a suitable tool for modeling complex drug metabolization reactions in vitro. Tamoxifen (TAM) was selected as a model substance due to its role as a prodrug widely used in breast cancer therapy, where its main active metabolite, endoxifen, arises from a two-step metabolism primarily involving the CYP system. Specifically, the combined activity of CYP3A4 and CYP2D6 is believed to be essential for efficient endoxifen production. However, the physiological metabolization pathway of TAM is more complex and interconnected, and the reasons for TAM’s therapeutic success and variability among patients are not yet fully understood. Analogous to our recently introduced mono-CYP3A4 CHO cells, we generated a CHO cell line expressing human CPR and CYP2D6, including analysis of CYP2D6 expression and specific activity. Comparative studies on the metabolization of TAM were performed with both mono-CYP CHO models individually and in co-culture with intact cells as well as with isolated microsomes. Supernatants were analyzed by HPLC to calculate individual CYP activity for each metabolite. All the picked mono-CYP2D6 clones expressed similar CYP2D6 protein amounts but showed different enzyme activities. Mono-CYP2D6 clone 18 was selected as the most suitable for TAM metabolization based on microsomal activity assays. TAM conversion with mono-CYP2D6 and -3A4 clones, as well as the combination of both, resulted in the formation of the expected main metabolites. Mono-CYP2D6 cells and microsomes produced the highest detected amounts of 4-hydroxytamoxifen and endoxifen, along with N-desmethyltamoxifen and small amounts of N,N-didesmethyltamoxifen. N-desmethyltamoxifen was the only TAM metabolite detected in notable quantities in mono-CYP3A4, while 4-hydroxytamoxifen and endoxifen were present only in trace amounts. In CYP2D6/3A4 co-culture and equal mixtures of both CYP microsomes, all metabolites were detected at concentrations around 50% of those in individual clones, indicating no significant synergistic effects. In conclusion, our mono-CYP CHO model confirmed the essential role of CYP2D6 in synthesizing the active TAM metabolite endoxifen and indicated that CYP2D6 is also involved in producing the by-metabolite N,N-didesmethyltamoxifen. The differences in metabolite spectra between the two mono-CYP models highlight the CYP specificity and sensitivity of our in vitro system. Full article
(This article belongs to the Special Issue Cytochrome P450: Metabolism, Structure-Function, Evolution and Applications)
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12 pages, 2022 KiB  
Article
Impact of Missense Mutations on AFB1 Metabolism in Bovine Cytochrome P4503A Isoforms: A Computational Mutagenesis and Molecular Docking Analysis
by Ludovica Montanucci, Silvia Iori, Maija Lahtela-Kakkonen, Marianna Pauletto, Mery Giantin and Mauro Dacasto
Int. J. Mol. Sci. 2024, 25(23), 12529; https://doi.org/10.3390/ijms252312529 - 22 Nov 2024
Viewed by 848
Abstract
Cytochrome P450 3A (CYP3A) enzymes catalyze the metabolism of a wide range of endogenous and exogenous compounds. Genetic variations in the 3 CYP3A isoforms (CYP3A28, CYP3A74, and CYP3A76) may influence their expression and activity, leading to inter-individual differences in xenobiotic metabolism. In domestic [...] Read more.
Cytochrome P450 3A (CYP3A) enzymes catalyze the metabolism of a wide range of endogenous and exogenous compounds. Genetic variations in the 3 CYP3A isoforms (CYP3A28, CYP3A74, and CYP3A76) may influence their expression and activity, leading to inter-individual differences in xenobiotic metabolism. In domestic cattle, understanding how genetic variations modulate CYP3A activity is crucial for both its therapeutic implications (clinical efficacy and adverse drug effects) and food safety (residues in foodstuff). Here, we updated the variant calling of CYP3As in 300 previously sequenced Piedmontese beef cattle, using the most recent reference genome, which contains an updated, longer sequence for CYP3A28. All but one previously identified missense variants were confirmed and a new variant, R105W in CYP3A28, was discovered. Through computational mutagenesis and molecular docking, we computationally predicted the impact of all identified CYP3A variant enzymes on protein stability and their affinity for aflatoxin B1 (AFB1), a potent carcinogen and food contaminant. For CYP3A28, we also computationally predicted its affinity for the probe substrate nifedipine (NIF). We found that CYP3A28 with R105W variant cannot accommodate NIF nor AFB1 in the binding pocket, thus affecting their metabolism. Our work provides computational foundation and prioritized ranking of CYP3A variants for future experimental validations. Full article
(This article belongs to the Special Issue Cytochrome P450: Metabolism, Structure-Function, Evolution and Applications)
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13 pages, 3826 KiB  
Article
The Effect of Metformin and Hydrochlorothiazide on Cytochrome P450 3A4 Metabolism of Ivermectin: Insights from In Silico Experimentation
by Thuli R. Mtambo, Kgothatso E. Machaba, Nireshni Chellan, Pritika Ramharack, Christo J. F. Muller, Ndumiso N. Mhlongo and Nokulunga Hlengwa
Int. J. Mol. Sci. 2024, 25(22), 12089; https://doi.org/10.3390/ijms252212089 - 11 Nov 2024
Viewed by 1371
Abstract
The spread of SARS-CoV-2 has led to an interest in using ivermectin (a potent antiparasitic agent) as an antiviral agent despite the lack of convincing in vivo clinical data for its use against COVID-19. The off-target prophylactic use of ivermectin adds a substantial [...] Read more.
The spread of SARS-CoV-2 has led to an interest in using ivermectin (a potent antiparasitic agent) as an antiviral agent despite the lack of convincing in vivo clinical data for its use against COVID-19. The off-target prophylactic use of ivermectin adds a substantial risk of drug–drug interactions with pharmaceutical medications used to treat chronic conditions like diabetes and hypertension (metformin and hydrochlorothiazide, respectively). Therefore, this study aims to evaluate the potential drug–drug interactions between ivermectin with either metformin or hydrochlorothiazide. In silico experiments and high-throughput screening assays for CYP3A4 were conducted to understand how metformin and hydrochlorothiazide might affect CYP3A4’s role in metabolizing ivermectin. The study findings indicated that hydrochlorothiazide is more stable than both ivermectin and metformin. This conclusion was further supported by root mean square fluctuation analysis, which showed that hydrochlorothiazide is more flexible. The variation in the principal component analysis scatter plot across the first three normal modes suggests hydrochlorothiazide has a more mobile conformation than ivermectin and metformin. Additionally, a strong inhibition of CYP3A4 by hydrochlorothiazide was observed, suggesting that hydrochlorothiazide’s regulatory effects could significantly impede CYP3A4 activity, potentially leading to a reduced metabolism and clearance of ivermectin in the body. Concurrent administration of these drugs may result in drug–drug interactions and hinder the hepatic metabolism of ivermectin. Full article
(This article belongs to the Special Issue Cytochrome P450: Metabolism, Structure-Function, Evolution and Applications)
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35 pages, 8530 KiB  
Article
Structure–Function Analysis of the Essential Mycobacterium tuberculosis P450 Drug Target, CYP121A1
by Tiara Padayachee, David C. Lamb, David R. Nelson and Khajamohiddin Syed
Int. J. Mol. Sci. 2024, 25(9), 4886; https://doi.org/10.3390/ijms25094886 - 30 Apr 2024
Cited by 3 | Viewed by 2018
Abstract
Cytochrome P450 CYP121A1 is a well-known drug target against Mycobacterium tuberculosis, the human pathogen that causes the deadly disease tuberculosis (TB). CYP121A1 is a unique P450 enzyme because it uses classical and non-classical P450 catalytic processes and has distinct structural features among [...] Read more.
Cytochrome P450 CYP121A1 is a well-known drug target against Mycobacterium tuberculosis, the human pathogen that causes the deadly disease tuberculosis (TB). CYP121A1 is a unique P450 enzyme because it uses classical and non-classical P450 catalytic processes and has distinct structural features among P450s. However, a detailed investigation of CYP121A1 protein structures in terms of active site cavity dynamics and key amino acids interacting with bound ligands has yet to be undertaken. To address this research knowledge gap, 53 CYP121A1 crystal structures were investigated in this study. Critical amino acids required for CYP121A1’s overall activity were identified and highlighted this enzyme’s rigid architecture and substrate selectivity. The CYP121A1-fluconazole crystal structure revealed a novel azole drug–P450 binding mode in which azole heme coordination was facilitated by a water molecule. Fragment-based inhibitor approaches revealed that CYP121A1 can be inhibited by molecules that block the substrate channel or by directly interacting with the P450 heme. This study serves as a reference for the precise understanding of CYP121A1 interactions with different ligands and the structure–function analysis of P450 enzymes in general. Our findings provide critical information for the synthesis of more specific CYP121A1 inhibitors and their development as novel anti-TB drugs. Full article
(This article belongs to the Special Issue Cytochrome P450: Metabolism, Structure-Function, Evolution and Applications)
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