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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 39970

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Prof. Dr. Bhagavatula Moorthy

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Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
Interests: cytochrome P450; Ah receptor; hyperoxic lung injury; ARDS; bronchopulmonary dysplasia; polycyclic aromatic hydrocarbons; carcinogenesis; oxidative stress
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Dr. Romi Ghose

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Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health Building 2, Room 7045, 4849 Calhoun Rd., Houston, TX 77204-5037, USA
Interests: regulation of drug metabolizing enzymes during inflammation; obesity and diseases; gastrointestinal toxicity of chemotherapy drugs; pharmacokinetic/pharmacodynamic studies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are in the midst of establishing a Special Issue on the hot topic “Cytochrome P450” for the journal IJMS. Cytochrome P450 (CYP) is a superfamily of enzymes that function as monooxygenases and contain heme as a cofactor. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds as well as for hormone synthesis and breakdown. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.

CYP enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, archaea, and even in viruses. More than 50,000 distinct CYP proteins are known. CYPs are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. There are 57 CYP isoforms in humans, and their role in human drug metabolism, including chemotherapeutic drugs, is well known. However, their role in the metabolism of endogenous substrates is not completely understood. Hence, there is a need for further research to elucidate the mechanisms of CYP regulation and the molecular role of CYP in the metabolism of drugs, nutrients, xenobiotics, and endogenous compounds.

Original manuscripts and reviews dealing with the regulation and role of CYP enzymes in metabolism of xenobiotics or endobiotics are invited for consideration, for publication in IJMS.

Prof. Dr. Bhagavatula Moorthy
Dr. Romi Ghose
Guest Editors

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Related Special Issue

Cytochrome P450 (CYP) 2.0 in International Journal of Molecular Sciences (2 articles)

Published Papers (10 papers)

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Research

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17 pages, 5600 KiB

Open AccessArticle

Effects of CYP3A43 Expression on Cell Proliferation and Migration of Lung Adenocarcinoma and Its Clinical Significance

by Qi-Yao Wei, Andy T. Y. Lau, Hai-Ying Mo, Qiu-Hua Zhong, Xiao-Yun Zhao, Fei-Yuan Yu, Jin Han, Yu-Yao Wu and Yan-Ming Xu

Int. J. Mol. Sci. 2023, 24(1), 113; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010113 - 21 Dec 2022

Cited by 4 | Viewed by 1893

Abstract

The cytochrome P450s (CYP450s) include key oxidative enzymes involved in the metabolism of various carcinogens and anticancer drugs. Bioinformatic studies have demonstrated the association of CYP3A43 with liver cancer and ovarian cancer. However, the biological function of CYP3A43 in tumor progression remains unclear. To further reveal the role of CYP3A43 in tumor progression, we first analyzed the data from the UALCAN database and found that CYP3A43 was negatively correlated to the cancer staging and lymph node metastasis of lung adenocarcinoma (LUAD). We established stable CYP3A43-knockdown LUAD H1299 cell line and found that its knockdown enhanced cell proliferation, colony formation, and migration in vitro, and promoted the growth of tumor xenograft in vivo. Interestingly, when CYP3A43 was ectopically-expressed in the LUAD cell lines, decreased cell proliferation and ERK1/2 phosphorylation level were observed. Lastly, we also identified CYP3A43 co-expressed genes in LUAD from LinkedOmics database followed by GO and KEGG analyses. In conclusion, our results indicate the unprecedented role of CYP3A43 in the suppression of LUAD and provide new possibilities for targeted therapy of this life-threatening disease. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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16 pages, 2524 KiB

Open AccessArticle

Structure-Dependent Toxicokinetics of Selected Pyrrolizidine Alkaloids In Vitro

by Julia Buchmueller, Florian Kaltner, Christoph Gottschalk, Maria Maares, Albert Braeuning and Stefanie Hessel-Pras

Int. J. Mol. Sci. 2022, 23(16), 9214; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169214 - 16 Aug 2022

Cited by 2 | Viewed by 1434

Abstract

Phytochemicals like pyrrolizidine alkaloids (PAs) can affect the health of humans and animals. PAs can occur for example in tea, honey or herbs. Some PAs are known to be cytotoxic, genotoxic, and carcinogenic. Upon intake of high amounts, hepatotoxic and pneumotoxic effects were observed in humans. This study aims to elucidate different toxicokinetic parameters like the uptake of PAs and their metabolism with in vitro models. We examined the transport rates of differently structured PAs (monoester, open-chained diester, cyclic diester) over a model of the intestinal barrier. After passing the intestinal barrier, PAs reach the liver, where they are metabolized into partially instable electrophilic metabolites interacting with nucleophilic centers. We investigated this process by the usage of human liver, intestinal, and lung microsomal preparations for incubation with different PAs. These results are completed with the detection of apoptosis as indicator for bioactivation of the PAs. Our results show a structure-dependent passage of PAs over the intestinal barrier. PAs are structure-dependently metabolized by liver microsomes and, to a smaller extent, by lung microsomes. The detection of apoptosis of A549 cells treated with lasiocarpine and monocrotaline following bioactivation by human liver or lung microsomes underlines this result. Conclusively, our results help to shape the picture of PA toxicokinetics which could further improve the knowledge of molecular processes leading to observed effects of PAs in vivo. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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27 pages, 7242 KiB

Open AccessArticle

Transgenic Expression of Haemonchus contortus Cytochrome P450 Hco-cyp-13A11 Decreases Susceptibility to Particular but Not All Macrocyclic Lactones in the Model Organism Caenorhabditis elegans

by Natalie Jakobs, Esra Yilmaz and Jürgen Krücken

Int. J. Mol. Sci. 2022, 23(16), 9155; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169155 - 15 Aug 2022

Cited by 2 | Viewed by 1597

Abstract

The number of reported macrocyclic lactones (ML) resistance cases across all livestock hosts is steadily increasing. Different studies in the parasitic nematode Haemonchus contortus assume the participation of cytochrome P450s (Cyps) enzymes in ML resistance. Still, functional data about their individual contribution to resistance or substrate specificity is missing. Via microinjection, transgenic Caenorhabditis elegans expressing HCON_00141052 (transgene-Hco-cyp-13A11) from extrachromosomal arrays were generated. After 24 h of exposure to different concentrations of ivermectin (IVM), ivermectin aglycone (IVMa), selamectin (SEL), doramectin (DRM), eprinomectin (EPR), and moxidectin (MOX), motility assays were performed to determine the impact of the H. contortus Cyp to the susceptibility of the worms against each ML. While transgene-Hco-cyp-13A11 significantly decreased susceptibility to IVM (four-fold), IVMa (2-fold), and SEL (3-fold), a slight effect for DRM and no effect for MOX, and EPR was observed. This substrate specificity of Hco-cyp-13A11 could not be explained by molecular modeling and docking studies. Hco-Cyp-13A11 molecular models were obtained for alleles from isolates with different resistance statuses. Although 14 amino acid polymorphisms were detected, none was resistance specific. In conclusion, Hco-cyp-13A11 decreased IVM, IVMa, and SEL susceptibility to a different extent, but its potential impact on ML resistance is not driven by polymorphisms. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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14 pages, 2807 KiB

Open AccessArticle

Co-Crystal Structure-Guided Optimization of Dual-Functional Small Molecules for Improving the Peroxygenase Activity of Cytochrome P450BM3

by Xiangquan Qin, Yiping Jiang, Jie Chen, Fuquan Yao, Panxia Zhao, Longyi Jin and Zhiqi Cong

Int. J. Mol. Sci. 2022, 23(14), 7901; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147901 - 18 Jul 2022

Cited by 9 | Viewed by 1648

Abstract

We recently developed an artificial P450–H₂O₂ system assisted by dual-functional small molecules (DFSMs) to modify the P450BM3 monooxygenase into its peroxygenase mode, which could be widely used for the oxidation of non-native substrates. Aiming to further improve the DFSM-facilitated P450–H₂O₂ system, a series of novel DFSMs having various unnatural amino acid groups was designed and synthesized, based on the co-crystal structure of P450BM3 and a typical DFSM, N-(ω-imidazolyl)-hexanoyl-L-phenylalanine, in this study. The size and hydrophobicity of the amino acid residue in the DFSM drastically affected the catalytic activity (up to 5-fold), stereoselectivity, and regioselectivity of the epoxidation and hydroxylation reactions. Docking simulations illustrated that the differential catalytic ability among the DFSMs is closely related to the binding affinity and the distance between the catalytic group and heme iron. This study not only enriches the DFSM toolbox to provide more options for utilizing the peroxide-shunt pathway of cytochrome P450BM3, but also sheds light on the great potential of the DFSM-driven P450 peroxygenase system in catalytic applications based on DFSM tunability. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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22 pages, 5866 KiB

Open AccessArticle

Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway

by Hai-Ying Mo, Qi-Yao Wei, Qiu-Hua Zhong, Xiao-Yun Zhao, Dan Guo, Jin Han, Wachiraporn Noracharttiyapot, Lydia Visser, Anke van den Berg, Yan-Ming Xu and Andy T. Y. Lau

Int. J. Mol. Sci. 2022, 23(14), 7853; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147853 - 16 Jul 2022

Cited by 4 | Viewed by 1962

Abstract

Cytochrome P450 enzymes (CYP450s) exert mighty catalytic actions in cellular metabolism and detoxication, which play pivotal roles in cell fate determination. Preliminary data shows differential expression levels of CYP27C1, one of the “orphan P450s” in human lung cancer cell lines. Here, we study the functions of CYP27C1 in lung cancer progression and drug endurance, and explore its potential to be a diagnostic and therapeutic target for lung cancer management. Quantitative real-time PCR and immunoblot assays were conducted to estimate the transcription and protein expression level of CYP27C1 in human lung cancer cell lines, which was relatively higher in A549 and H1975 cells, but was lower in H460 cells. Stable CYP27C1-knockdown A549 and H1975 cell lines were established, in which these cells showed enhancement in cell proliferation, colony formation, and migration. In addition, aberrant IGF-1R/Akt/p53 signal transduction was also detected in stable CYP27C1-knockdown human lung cancer cells, which exhibited greater tolerance towards the treatments of anticancer agents (including vinorelbine, picropodophyllin, pacritinib, and SKLB610). This work, for the first time, reveals that CYP27C1 impacts lung cancer cell development by participating in the regulation of the IGF-1R/Akt/p53 signaling pathway, and the level of CYP27C1 plays indispensable roles in dictating the cellular sensitivity towards multiple anticancer agents. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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31 pages, 1451 KiB

Open AccessArticle

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

by Michela Cantiello, Monica Carletti, Mery Giantin, Giulia Gardini, Francesca Capolongo, Paolo Cascio, Marianna Pauletto, Flavia Girolami, Mauro Dacasto and Carlo Nebbia

Int. J. Mol. Sci. 2022, 23(7), 3564; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073564 - 24 Mar 2022

Cited by 5 | Viewed by 3328

Abstract

In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB’s post-transcriptional effects are actually available. This work provides the first, and an almost complete, characterization of PB-dependent changes in DME catalytic activities in bovine liver using common probe substrates and confirmatory immunoblotting investigations. As expected, PB increased the total cytochrome P450 (CYP) content and the extent of metyrapone binding; moreover, an augmentation of protein amounts and related enzyme activities was observed for known PB targets such as CYP2B, 2C, and 3A, but also CYP2E1. However, contradictory results were obtained for CYP1A, while a decreased catalytic activity was observed for flavin-containing monooxygenases 1 and 3. The barbiturate had no effect on the chosen hydrolytic and conjugative DMEs. For the first time, we also measured the 26S proteasome activity, and the increase observed in PB-treated cattle would suggest this post-translational event might contribute to cattle DME regulation. Overall, this study increased the knowledge of cattle hepatic drug metabolism, and further confirmed the presence of species differences in DME expression and activity between cattle, humans, and rodents. This reinforced the need for an extensive characterization and understanding of comparative molecular mechanisms involved in expression, regulation, and function of DMEs. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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17 pages, 10547 KiB

Open AccessArticle

Genome-Wide Identification of CYP72A Gene Family and Expression Patterns Related to Jasmonic Acid Treatment and Steroidal Saponin Accumulation in Dioscorea zingiberensis

by Lixiu Hou, Xincheng Yuan, Song Li, Yi Li, Zihao Li and Jiaru Li

Int. J. Mol. Sci. 2021, 22(20), 10953; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010953 - 11 Oct 2021

Cited by 8 | Viewed by 2071

Abstract

Dioscorea zingiberensis is a medicinal herb containing a large amount of steroidal saponins, which are the major bioactive compounds and the primary storage form of diosgenin. The CYP72A gene family, belonging to cytochromes P450, exerts indispensable effects on the biosynthesis of numerous bioactive compounds. In this work, a total of 25 CYP72A genes were identified in D. zingiberensis and categorized into two groups according to the homology of protein sequences. The characteristics of their phylogenetic relationship, intron–exon organization, conserved motifs and cis-regulatory elements were performed by bioinformatics methods. The transcriptome data demonstrated that expression patterns of DzCYP72As varied by tissues. Moreover, qRT-PCR results displayed diverse expression profiles of DzCYP72As under different concentrations of jasmonic acid (JA). Likewise, eight metabolites in the biosynthesis pathway of steroidal saponins (four phytosterols, diosgenin, parvifloside, protodeltonin and dioscin) exhibited different contents under different concentrations of JA, and the content of total steroidal saponin was largest at the dose of 100 μmol/L of JA. The redundant analysis showed that 12 DzCYP72As had a strong correlation with specialized metabolites. Those genes were negatively correlated with stigmasterol and cholesterol but positively correlated with six other specialized metabolites. Among all DzCYP72As evaluated, DzCYP72A6, DzCYP72A16 and DzCYP72A17 contributed the most to the variation of specialized metabolites in the biosynthesis pathway of steroidal saponins. This study provides valuable information for further research on the biological functions related to steroidal saponin biosynthesis. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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Review

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13 pages, 603 KiB

Open AccessReview

Computer-Aided (In Silico) Modeling of Cytochrome P450-Mediated Food–Drug Interactions (FDI)

by Yelena Guttman and Zohar Kerem

Int. J. Mol. Sci. 2022, 23(15), 8498; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158498 - 31 Jul 2022

Cited by 8 | Viewed by 2364

Abstract

Modifications of the activity of Cytochrome 450 (CYP) enzymes by compounds in food might impair medical treatments. These CYP-mediated food–drug interactions (FDI) play a major role in drug clearance in the intestine and liver. Inter-individual variation in both CYP expression and structure is an important determinant of FDI. Traditional targeted approaches have highlighted a limited number of dietary inhibitors and single-nucleotide variations (SNVs), each determining personal CYP activity and inhibition. These approaches are costly in time, money and labor. Here, we review computational tools and databases that are already available and are relevant to predicting CYP-mediated FDIs. Computer-aided approaches such as protein–ligand interaction modeling and the virtual screening of big data narrow down hundreds of thousands of items in databanks to a few putative targets, to which the research resources could be further directed. Structure-based methods are used to explore the structural nature of the interaction between compounds and CYP enzymes. However, while collections of chemical, biochemical and genetic data are available today and call for the implementation of big-data approaches, ligand-based machine-learning approaches for virtual screening are still scarcely used for FDI studies. This review of CYP-mediated FDIs promises to attract scientists and the general public. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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16 pages, 1800 KiB

Open AccessReview

Cytochrome P450 Enzymes and Drug Metabolism in Humans

by Mingzhe Zhao, Jingsong Ma, Mo Li, Yingtian Zhang, Bixuan Jiang, Xianglong Zhao, Cong Huai, Lu Shen, Na Zhang, Lin He and Shengying Qin

Int. J. Mol. Sci. 2021, 22(23), 12808; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312808 - 26 Nov 2021

Cited by 184 | Viewed by 20122

Abstract

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1–3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy. Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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15 pages, 590 KiB

Open AccessReview

Genetic and Enzymatic Characteristics of CYP2A13 in Relation to Lung Damage

by Radim Vrzal

Int. J. Mol. Sci. 2021, 22(22), 12306; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212306 - 14 Nov 2021

Cited by 2 | Viewed by 2069

Abstract

Cytochrome P450 2A13 is an omitted brother of CYP2A6 that has an important role in the drug metabolism of liver. Due to extrahepatic expression, it has gained less attention than CYP2A6, despite the fact that it plays a significant role in toxicant-induced pulmonary lesions and, therefore, lung cancer. The purpose of this mini-review is to summarize the basic knowledge about this enzyme in relation to the substrates, inhibitors, genetic polymorphisms, and transcriptional regulation that are known so far (September 2021). Full article

(This article belongs to the Special Issue Cytochrome P450 (CYP))

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