Research advances in cytochrome P450-catalysed pharmaceutical terpenoid biosynthesis in plants

Advances in the role of cytochrome P450s in pharmaceutical terpenoid biosynthesis are reviewed, and different cloning strategies to identify new cytochrome P450 genes in the biosynthesis of natural terpenoids are summarized.

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Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation

Pharmaceutics ◽

10.3390/pharmaceutics10030112 ◽

2018 ◽

Vol 10 (3) ◽

pp. 112 ◽

Cited By ~ 6

Author(s):

Riya Shrestha ◽

Pil Cho ◽

Sanjita Paudel ◽

Aarajana Shrestha ◽

Mi Kang ◽

...

Keyword(s):

Cytochrome P450 ◽

Active Metabolite ◽

Experimental Studies ◽

Liver Microsomes ◽

Cytochrome P450s ◽

Hydroxylated Metabolites ◽

Udp Glucuronosyltransferase ◽

Cyp Isoforms ◽

Propionic Acid Derivative

Loxoprofen, a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced to its active metabolite, trans-alcohol form (Trans-OH) by carbonyl reductase enzyme in the liver. Previous studies demonstrated the hydroxylation and glucuronidation of loxoprofen. However, the specific enzymes catalyzing its metabolism have yet to be identified. In the present study, we investigated metabolic enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which are involved in the metabolism of loxoprofen. Eight microsomal metabolites of loxoprofen were identified, including two alcohol metabolites (M1 and M2), two mono-hydroxylated metabolites (M3 and M4), and four glucuronide conjugates (M5, M6, M7, and M8). Based on the results for the formation of metabolites when incubated in dexamethasone-induced microsomes, incubation with ketoconazole, and human recombinant cDNA-expressed cytochrome P450s, we identified CYP3A4 and CYP3A5 as the major CYP isoforms involved in the hydroxylation of loxoprofen (M3 and M4). Moreover, we identified that UGT2B7 is the major UGT isoform catalyzing the glucuronidation of loxoprofen and its alcoholic metabolites. Further experimental studies should be carried out to determine the potency and toxicity of these identified metabolites of loxoprofen, in order to fully understand of mechanism of loxoprofen toxicity.

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Interaction of prostacyclin synthase with cytochromes P450

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20196501063 ◽

2019 ◽

Vol 65 (1) ◽

pp. 63-66

Author(s):

O.V. Gnedenko ◽

E.O. Yablokov ◽

P.V. Ershov ◽

A.V. Svirid ◽

T.V. Shkel ◽

...

Keyword(s):

Cytochrome P450 ◽

Essential Role ◽

Protein Complexes ◽

Cytochromes P450 ◽

Thromboxane A2 ◽

Cytochrome P450s ◽

Cytochrome P450 Monooxygenase ◽

P450 Monooxygenase ◽

Prostacyclin Synthase

Biosensor experiments on investigation of interaction between prostacyclin synthase (PGIS) and different proteins of the cytochrome P450 monooxygenase systems were perfomed. Interaction of PGIS with microsomal (CYP21A2, CYP2E1) and mitochondrial (CYP27A1, CYP11B1, CYP11B2, CYP11A1) cytochrome P450s was detected. Kinetic and equilibrium parameters of protein complexes formation were determined. Data obtained suggest an essential role of these hemoproteins interaction in regulation of prostacyclin and thromboxane A2 biosynthesis.

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Role of cytochrome P450s in the male reproductive toxicity of 1-bromopropane

Toxicology Research ◽

10.1039/c6tx00164e ◽

2016 ◽

Vol 5 (6) ◽

pp. 1522-1529

Author(s):

Cai Zong ◽

Xiao Zhang ◽

Chinyen Huang ◽

Jie Chang ◽

C. Edwin Garner ◽

...

Keyword(s):

Cytochrome P450 ◽

Reproductive Toxicity ◽

Cytochrome P450s

Cytochrome P450 contributes to male reproductive toxicity of 1-bromopropane.

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The Role of Cytochrome P450s in Insect Toxicology and Resistance

Annual Review of Entomology ◽

10.1146/annurev-ento-070621-061328 ◽

2021 ◽

Vol 67 (1) ◽

Author(s):

Ralf Nauen ◽

Chris Bass ◽

René Feyereisen ◽

John Vontas

Keyword(s):

Cytochrome P450 ◽

Insecticide Resistance ◽

Insect Pests ◽

Cytochrome P450s ◽

Cytochrome P450 Monooxygenases ◽

Annual Review ◽

Publication Date ◽

Beneficial Insects ◽

P450 Monooxygenases

Insect cytochrome P450 monooxygenases (P450s) perform a variety of important physiological functions, but it is their role in the detoxification of xenobiotics, such as natural and synthetic insecticides, that is the topic of this review. Recent advances in insect genomics and postgenomic functional approaches have provided an unprecedented opportunity to understand the evolution of insect P450s and their role in insect toxicology. These approaches have also been harnessed to provide new insights into the genomic alterations that lead to insecticide resistance, the mechanisms by which P450s are regulated, and the functional determinants of P450-mediated insecticide resistance. In parallel, an emerging body of work on the role of P450s in defining the sensitivity of beneficial insects to insecticides has been developed. The knowledge gained from these studies has applications for the management of P450-mediated resistance in insect pests and can be leveraged to safeguard the health of important beneficial insects. Expected final online publication date for the Annual Review of Entomology, Volume 67 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Transcriptome-wide identification, characterization, and phylogenomic analysis of cytochrome P450s from Nothapodytes nimmoniana reveal candidate genes involved in the camptothecin biosynthetic pathway

Genome ◽

10.1139/gen-2020-0067 ◽

2021 ◽

Vol 64 (1) ◽

pp. 1-14

Author(s):

Rucha C. Godbole ◽

Anupama A. Pable ◽

Vitthal T. Barvkar

Keyword(s):

Cytochrome P450 ◽

Biosynthetic Pathway ◽

Expression Profiles ◽

Cytochrome P450s ◽

Phylogenomic Analysis ◽

Cytochrome P450 Enzymes ◽

Nothapodytes Nimmoniana ◽

Cytochrome P450 Genes ◽

Root Tissues ◽

Anticancer Compound

The plant Nothapodytes nimmoniana is an important source of camptothecin (CPT), an anticancer compound widely used in the treatment of colorectal, lung, and ovarian cancers. CPT is biosynthesized by the combination of the seco-iridoid and indole pathways in plants. The majority of the biosynthetic steps and associated genes still remain unknown. Certain reactions in the seco-iridoid pathway are catalyzed by cytochrome P450 enzymes. Hence, identifying transcriptionally active cytochrome P450 genes becomes essential in the elucidation of the CPT biosynthetic pathway. Here, we report the identification of 94 cytochrome P450s from the assembled transcriptomic data from leaf and root tissues of N. nimmoniana. The identified cytochrome P450 genes were full length and possessed all four conserved characteristic signature motifs of cytochrome P450 genes. Phylogenetic analysis of the protein sequences revealed their evolution and diversification and further categorized them into A-type (52.12%) and non-A-type (47.87%) cytochrome P450s. These 94 sequences represent 38 families and 63 subfamilies of cytochrome P450s. We also compared the transcriptional activity of identified cytochrome P450s with the expression of their homologs in the CPT-producing plant Ophiorrhiza pumila. Based on expression profiles and quantitative PCR validation, we propose NnCYP81CB1 and NnCYP89R1 as candidate cytochrome P450 genes involved in camptothecin biosynthesis in N. nimmoniana.

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Role of Hepatic Cytochrome P450s in the Pharmacokinetics and Toxicity of Cyclophosphamide: Studies with the Hepatic Cytochrome P450 Reductase Null Mouse

Cancer Research ◽

10.1158/0008-5472.can-04-4103 ◽

2005 ◽

Vol 65 (10) ◽

pp. 4211-4217 ◽

Cited By ~ 83

Author(s):

Georgia J. Pass ◽

Dianne Carrie ◽

Michael Boylan ◽

Sally Lorimore ◽

Eric Wright ◽

...

Keyword(s):

Cytochrome P450 ◽

Cytochrome P450s ◽

Null Mouse ◽

Cytochrome P450 Reductase ◽

P450 Reductase ◽

Hepatic Cytochrome

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Role of cytochrome P450 genes of Trichoderma atroviride T23 on the resistance and degradation of dichlorvos

Chemosphere ◽

10.1016/j.chemosphere.2021.133173 ◽

2021 ◽

pp. 133173

Author(s):

Jianan Sun ◽

Valliappan Karuppiah ◽

Yaqian Li ◽

Pandian Sivakumar ◽

Subramanian Kumaran ◽

...

Keyword(s):

Cytochrome P450 ◽

Trichoderma Atroviride ◽

Cytochrome P450 Genes

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Probing the Role of the Hinge Segment of Cytochrome P450 Oxidoreductase in the Interaction with Cytochrome P450

International Journal of Molecular Sciences ◽

10.3390/ijms19123914 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3914 ◽

Cited By ~ 3

Author(s):

Diana Campelo ◽

Francisco Esteves ◽

Bernardo Brito Palma ◽

Bruno Costa Gomes ◽

José Rueff ◽

...

Keyword(s):

Cytochrome P450 ◽

Cytochrome B5 ◽

Cytochrome P450s ◽

Cytochrome P450 Reductase ◽

Redox Partner ◽

Redox Partners ◽

Cytochrome P450 Oxidoreductase ◽

Experimental Approaches ◽

Menten Kinetic

NADPH-cytochrome P450 reductase (CPR) is the unique redox partner of microsomal cytochrome P450s (CYPs). CPR exists in a conformational equilibrium between open and closed conformations throughout its electron transfer (ET) function. Previously, we have shown that electrostatic and flexibility properties of the hinge segment of CPR are critical for ET. Three mutants of human CPR were studied (S243P, I245P and R246A) and combined with representative human drug-metabolizing CYPs (isoforms 1A2, 2A6 and 3A4). To probe the effect of these hinge mutations different experimental approaches were employed: CYP bioactivation capacity of pre-carcinogens, enzyme kinetic analysis, and effect of the ionic strength and cytochrome b5 (CYB5) on CYP activity. The hinge mutations influenced the bioactivation of pre-carcinogens, which seemed CYP isoform and substrate dependent. The deviations of Michaelis-Menten kinetic parameters uncovered tend to confirm this discrepancy, which was confirmed by CYP and hinge mutant specific salt/activity profiles. CPR/CYB5 competition experiments indicated a less important role of affinity in CPR/CYP interaction. Overall, our data suggest that the highly flexible hinge of CPR is responsible for the existence of a conformational aggregate of different open CPR conformers enabling ET-interaction with structural varied redox partners.

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