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Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 22193

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Dr. Patrick M. Dansette

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Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 45 Rue des Saints-Pères, CEDEX 06, 75270 Paris, 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.
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Dr. Arthur Roberts

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Department of Pharmaceutical Biomedical Sciences, The University of Georgia, Athens, GA 30602, USA
Interests: cytochrome P450
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous three Special Issues, “Cytochromes P450: Drug Metabolism and Bioactivation”, “Cytochrome P450: Drug Metabolism and Bioactivation and Biodiversity 2.0” and “Cytochrome P450: Drug Metabolism and Bioactivation and Biodiversity 3.0” (https://www.mdpi.com/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, 2 and 3 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 fourth 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
Dr. Arthur Roberts
Guest Editors

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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
drug metabolism
bioactivation
pharmacogenomics
reactive intermediates
drug induced toxicity
reaction mechanisms

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Published Papers (10 papers)

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16 pages, 2269 KiB

Open AccessArticle

Evolution of Cytochrome P450 Enzymes and Their Redox Partners in Archaea

by Phelelani Erick Ngcobo, Bridget Valeria Zinhle Nkosi, Wanping Chen, David R. Nelson and Khajamohiddin Syed

Int. J. Mol. Sci. 2023, 24(4), 4161; https://doi.org/10.3390/ijms24044161 - 19 Feb 2023

Cited by 14 | Viewed by 3508

Abstract

Cytochrome P450 monooxygenases (CYPs/P450s) and their redox partners, ferredoxins, are ubiquitous in organisms. P450s have been studied in biology for over six decades owing to their distinct catalytic activities, including their role in drug metabolism. Ferredoxins are ancient proteins involved in oxidation-reduction reactions, such as transferring electrons to P450s. The evolution and diversification of P450s in various organisms have received little attention and no information is available for archaea. This study is aimed at addressing this research gap. Genome-wide analysis revealed 1204 P450s belonging to 34 P450 families and 112 P450 subfamilies, where some families and subfamilies are expanded in archaea. We also identified 353 ferredoxins belonging to the four types 2Fe-2S, 3Fe-4S, 7Fe-4S and 2[4Fe-4S] in 40 archaeal species. We found that bacteria and archaea shared the CYP109, CYP147 and CYP197 families, as well as several ferredoxin subtypes, and that these genes are co-present on archaeal plasmids and chromosomes, implying the plasmid-mediated lateral transfer of these genes from bacteria to archaea. The absence of ferredoxins and ferredoxin reductases in the P450 operons suggests that the lateral transfer of these genes is independent. We present different scenarios for the evolution and diversification of P450s and ferredoxins in archaea. Based on the phylogenetic analysis and high affinity to diverged P450s, we propose that archaeal P450s could have diverged from CYP109, CYP147 and CYP197. Based on this study’s results, we propose that all archaeal P450s are bacterial in origin and that the original archaea had no P450s. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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13 pages, 3290 KiB

Open AccessArticle

Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina

by Yoshinori Sato, Wenjing Dong, Tatsuro Nakamura, Naohiro Mizoguchi, Tasuku Nawaji, Miyu Nishikawa, Takenori Onaga, Shinichi Ikushiro, Makoto Kobayashi and Hiroki Teraoka

Int. J. Mol. Sci. 2023, 24(4), 4013; https://doi.org/10.3390/ijms24044013 - 16 Feb 2023

Cited by 3 | Viewed by 2642

Abstract

Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a β-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [−]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [−] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [−] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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17 pages, 2807 KiB

Open AccessArticle

Distinct Mechanistic Behaviour of Tomato CYP74C3 and Maize CYP74A19 Allene Oxide Synthases: Insights from Trapping Experiments and Allene Oxide Isolation

by Alexander N. Grechkin, Natalia V. Lantsova, Lucia S. Mukhtarova, Bulat I. Khairutdinov, Svetlana S. Gorina, Tatiana M. Iljina and Yana Y. Toporkova

Int. J. Mol. Sci. 2023, 24(3), 2230; https://doi.org/10.3390/ijms24032230 - 23 Jan 2023

Cited by 1 | Viewed by 1555

Abstract

The product specificity and mechanistic peculiarities of two allene oxide synthases, tomato LeAOS3 (CYP74C3) and maize ZmAOS (CYP74A19), were studied. Enzymes were vortexed with linoleic acid 9-hydroperoxide in a hexane–water biphasic system (20–60 s, 0 °C). Synthesized allene oxide (9,10-epoxy-10,12-octadecadienoic acid; 9,10-EOD) was trapped with ethanol. Incubations with ZmAOS produced predominantly 9,10-EOD, which was converted into an ethanolysis product, (12Z)-9-ethoxy-10-oxo-12-octadecenoic acid. LeAOS3 produced the same trapping product and 9(R)–α–ketol at nearly equimolar yields. Thus, both α–ketol and 9,10-EOD appeared to be kinetically controlled LeAOS3 products. NMR data for 9,10-EOD (Me) preparations revealed that ZmAOS specifically synthesized 10(E)-9,10-EOD, whereas LeAOS3 produced a roughly 4:1 mixture of 10(E) and 10(Z) isomers. The cyclopentenone cis-10-oxo-11-phytoenoic acid (10-oxo-PEA) and the Favorskii-type product yields were appreciable with LeAOS3, but dramatically lower with ZmAOS. The 9,10-EOD (free acid) kept in hexane transformed into macrolactones but did not cyclize. LeAOS3 catalysis is supposed to produce a higher proportion of oxyallyl diradical (a valence tautomer of allene oxide), which is a direct precursor of both cyclopentenone and cyclopropanone. This may explain the substantial yields of cis-10-oxo-PEA and the Favorskii-type product (via cyclopropanone) with LeAOS3. Furthermore, 10(Z)-9,10-EOD may be produced via the reverse formation of allene oxide from oxyallyl diradical. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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14 pages, 1696 KiB

Open AccessArticle

Saprophytic to Pathogenic Mycobacteria: Loss of Cytochrome P450s Vis a Vis Their Prominent Involvement in Natural Metabolite Biosynthesis

by Ntokozo Minenhle Zondo, Tiara Padayachee, David R. Nelson and Khajamohiddin Syed

Int. J. Mol. Sci. 2023, 24(1), 149; https://doi.org/10.3390/ijms24010149 - 21 Dec 2022

Cited by 10 | Viewed by 1786

Abstract

Cytochrome P450 monooxygenases (P450s/CYPs) are ubiquitous enzymes with unique regio- and stereo-selective oxidation activities. Due to these properties, P450s play a key role in the biosynthesis of natural metabolites. Mycobacterial species are well-known producers of complex metabolites that help them survive in diverse ecological niches, including in the host. In this study, a comprehensive analysis of P450s and their role in natural metabolite synthesis in 2666 mycobacterial species was carried out. The study revealed the presence of 62,815 P450s that can be grouped into 182 P450 families and 345 subfamilies. Blooming (the presence of more than one copy of the same gene) and expansion (presence of the same gene in many species) were observed at the family and subfamily levels. CYP135 was the dominant family in mycobacterial species. The mycobacterial species have distinct P450 profiles, indicating that lifestyle impacts P450 content in their genome vis a vis P450s, playing a key role in organisms’ adaptation. Analysis of the P450 profile revealed a gradual loss of P450s from non-pathogenic to pathogenic mycobacteria. Pathogenic mycobacteria have more P450s in biosynthetic gene clusters that produce natural metabolites. This indicates that P450s are recruited for the biosynthesis of unique metabolites, thus helping these pathogens survive in their niches. This study is the first to analyze P450s and their role in natural metabolite synthesis in many mycobacterial species. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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9 pages, 1749 KiB

Open AccessCommunication

Human Orphan Cytochrome P450 2U1 Catalyzes the ω-Hydroxylation of Leukotriene B₄

by Khawla Nouri, Nicolas Pietrancosta, Laurent Le Corre, Patrick M. Dansette, Daniel Mansuy and Jean-Luc Boucher

Int. J. Mol. Sci. 2022, 23(23), 14615; https://doi.org/10.3390/ijms232314615 - 23 Nov 2022

Cited by 1 | Viewed by 1422

Abstract

Cytochrome P450 2U1 (CYP2U1) identified from the human genome remains poorly known since few data are presently available on its physiological function(s) and substrate(s) specificity. CYP2U1 mutations are associated with complicated forms of hereditary spastic paraplegia, alterations of mitochondrial architecture and bioenergetics. In order to better know the biological roles of CYP2U1, we used a bioinformatics approach. The analysis of the data invited us to focus on leukotriene B₄ (LTB₄), an important inflammatory mediator. Here, we show that CYP2U1 efficiently catalyzes the hydroxylation of LTB₄ predominantly on its ω-position. We also report docking experiments of LTB₄ in a 3D model of truncated CYP2U1 that are in agreement with this hydroxylation regioselectivity. The involvement of CYP2U1 in the metabolism of LTB₄ could have strong physiological consequences in cerebral pathologies including ischemic stroke because CYP2U1 is predominantly expressed in the brain. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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13 pages, 1604 KiB

Open AccessArticle

The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain

by Anna Haduch, Ewa Bromek, Renata Pukło, Joanna Jastrzębska, Przemysław Jan Danek and Władysława Anna Daniel

Int. J. Mol. Sci. 2022, 23(22), 13746; https://doi.org/10.3390/ijms232213746 - 8 Nov 2022

Cited by 3 | Viewed by 1804

Abstract

The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D. Five-day treatment with CP-101,606 increased the activity and protein level of CYP2D in the hippocampus. That effect was maintained after the 3-week treatment and was accompanied by enhancement in the CYP2D activity/protein level in the cortex and cerebellum. In contrast, a 3-week treatment with CP-101,606 diminished the CYP2D activity/protein level in the hypothalamus and striatum. In the liver, CP-101,606 decreased CYP2D activity, but not the protein or mRNA level, after 5-day or 3-week treatment. When added in vitro to liver microsomes, CP-101,606 diminished the CYP2D activity during prolonged incubation. While in the brain, the observed decrease in the CYP2D activity after short- and long-term treatment with CP-101,606 seems to be a consequence of the drug effect on enzyme regulation. In the liver, the direct inhibitory effect of reactive metabolites formed from CP-101,606 on the CYP2D activity may be considered. Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances, it can be assumed that apart from antagonizing the NMDA receptor, CP-101,606 may modify its own pharmacological effect by affecting brain cytochrome P450. On the other hand, an inhibition of the activity of liver CYP2D may slow down the metabolism of co-administered substrates and lead to pharmacokinetic drug–drug interactions. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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14 pages, 3371 KiB

Open AccessArticle

Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site

by Irina F. Sevrioukova

Int. J. Mol. Sci. 2022, 23(20), 12591; https://doi.org/10.3390/ijms232012591 - 20 Oct 2022

Cited by 5 | Viewed by 2084

Abstract

Cytochrome P450 3A4 (CYP3A4) is a major human drug-metabolizing enzyme, notoriously known for its extreme substrate promiscuity, allosteric behavior, and implications in drug–drug interactions. Despite extensive investigations, the mechanism of ligand binding to CYP3A4 is not fully understood. We determined the crystal structure of CYP3A4 complexed with fluorol, a small fluorescent dye that can undergo hydroxylation. In the structure, fluorol associates to the substrate channel, well suited for the binding of planar polyaromatic molecules bearing polar groups, through which stabilizing H-bonds with the polar channel residues, such as Thr224 and Arg372, can be established. Mutagenesis, spectral, kinetic, and functional data confirmed the involvement but not strict requirement of Thr224 for the association of fluorol. Collectively, our data identify the substrate channel as a high-affinity ligand binding site and support the notion that hydrophobic ligands first dock to the nearby peripheral surface, before migrating to the channel and, subsequently, into the active site. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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12 pages, 2310 KiB

Open AccessArticle

Detection of Unprecedented CYP74 Enzyme in Mammal: Hydroperoxide Lyase CYP74C44 of the Bat Sturnira hondurensis

by Svetlana S. Gorina, Tatiana M. Iljina, Lucia S. Mukhtarova, Yana Y. Toporkova and Alexander N. Grechkin

Int. J. Mol. Sci. 2022, 23(14), 8009; https://doi.org/10.3390/ijms23148009 - 20 Jul 2022

Cited by 2 | Viewed by 1424

Abstract

The genome of the neotropical fruit bat Sturnira hondurensis was recently sequenced, revealing an unexpected gene encoding a plant-like protein, CYP74C44, which shares ca. 90% sequence identity with the putative CYP74C of Populus trichocarpa. The preparation and properties of the recombinant CYP74C44 are described in the present work. The CYP74C44 enzyme was found to be active against the 13- and 9-hydroperoxides of linoleic and α-linolenic acids (13-HPOD, 13-HPOT, 9-HPOD, and 9-HPOT, respectively), as well as the 15-hydroperoxide of eicosapentaenoic acid (15-HPEPE). All substrates studied were specifically transformed into chain cleavage products that are typical for hydroperoxide lyases (HPLs). The HPL chain cleavage reaction was validated by the identification of NaBH₄-reduced products (Me/TMS) of 15-HPEPE and 13- and 9-hydroperoxides as (all-Z)-14-hydroxy-5,8,11-tetradecatrienoic, (9Z)-12-hydroxy-9-dodecenoic, and 9-hydroxynonanoic acids (Me/TMS), respectively. Thus, CYP74C44 possessed the HPL activity that is typical for the CYP74C subfamily proteins. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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24 pages, 5187 KiB

Open AccessArticle

Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment

by Eric R. Samuels and Irina F. Sevrioukova

Int. J. Mol. Sci. 2022, 23(13), 7291; https://doi.org/10.3390/ijms23137291 - 30 Jun 2022

Cited by 3 | Viewed by 1906

Abstract

Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure–activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers’ length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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Review

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21 pages, 1656 KiB

Open AccessReview

Spotlight on CYP4B1

by Annika Röder, Saskia Hüsken, Michael C. Hutter, Allan E. Rettie, Helmut Hanenberg, Constanze Wiek and Marco Girhard

Int. J. Mol. Sci. 2023, 24(3), 2038; https://doi.org/10.3390/ijms24032038 - 20 Jan 2023

Cited by 5 | Viewed by 3155

Abstract

The mammalian cytochrome P450 monooxygenase CYP4B1 can bioactivate a wide range of xenobiotics, such as its defining/hallmark substrate 4-ipomeanol leading to tissue-specific toxicities. Similar to other members of the CYP4 family, CYP4B1 has the ability to hydroxylate fatty acids and fatty alcohols. Structural insights into the enigmatic role of CYP4B1 with functions in both, xenobiotic and endobiotic metabolism, as well as its unusual heme-binding characteristics are now possible by the recently solved crystal structures of native rabbit CYP4B1 and the p.E310A variant. Importantly, CYP4B1 does not play a major role in hepatic P450-catalyzed phase I drug metabolism due to its predominant extra-hepatic expression, mainly in the lung. In addition, no catalytic activity of human CYP4B1 has been observed owing to a unique substitution of an evolutionary strongly conserved proline 427 to serine. Nevertheless, association of CYP4B1 expression patterns with various cancers and potential roles in cancer development have been reported for the human enzyme. This review will summarize the current status of CYP4B1 research with a spotlight on its roles in the metabolism of endogenous and exogenous compounds, structural properties, and cancer association, as well as its potential application in suicide gene approaches for targeted cancer therapy. Full article

(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 4.0)

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