Simultaneously Assessing Concentration Changes in 17 Biochemical Pathways as a Result of Drug Dosing and Cytochrome P450 and Non-cytochrome P450-Mediated Metabolism: A Quasi-Untargeted Metabolomics LC/MS Assay

2021 ◽  
pp. 341-357
Author(s):  
John A. Masucci ◽  
Feng Liang ◽  
Kerem Bingol ◽  
Vince Windisch ◽  
Gary W. Caldwell
Keyword(s):  
Cytochrome P450 ◽  
Untargeted Metabolomics ◽  
Drug Dosing ◽  
Biochemical Pathways ◽  
Concentration Changes

scholarly journals Frequency of Important CYP450 Enzyme Gene Polymorphisms in the Iranian Population in Comparison with Other Major Populations: A Comprehensive Review of the Human Data

2021 ◽  
Vol 11 (8) ◽  
pp. 804
Author(s):  
Navid Neyshaburinezhad ◽  
Hengameh Ghasim ◽  
Mohammadreza Rouini ◽  
Youssef Daali ◽  
Yalda H. Ardakani
Keyword(s):  
Cytochrome P450 ◽  
Meta Analysis ◽  
Clinical Importance ◽  
Copy Number Variations ◽  
Iranian Population ◽  
Human Populations ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Drug Dosing ◽  
Linkage Information

Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated.

Biodiversity of cytochrome P450 redox systems

2005 ◽  
Vol 33 (4) ◽  
pp. 796-801 ◽  
Author(s):  
K.J. McLean ◽  
M. Sabri ◽  
K.R. Marshall ◽  
R.J. Lawson ◽  
D.G. Lewis ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cytochrome P450 ◽  
Redox Systems ◽  
Remarkable Similarity ◽  
Biochemical Pathways ◽  
Redox Partner ◽  
Recent Advances ◽  
Wide Range ◽  
Domains Of Life

P450s (cytochrome P450 mono-oxygenases) are a superfamily of haem-containing mono-oxygenase enzymes that participate in a wide range of biochemical pathways in different organisms from all of the domains of life. To facilitate their activity, P450s require sequential delivery of two electrons passed from one or more redox partner enzymes. Although the P450 enzymes themselves show remarkable similarity in overall structure, it is increasingly apparent that there is enormous diversity in the redox partner systems that drive the P450 enzymes. This paper examines some of the recent advances in our understanding of the biodiversity of the P450 redox apparatus, with a particular emphasis on the redox systems in the pathogen Mycobacterium tuberculosis.

Fe-N-C Nanozyme with Both Accelerated and Inhibited Biocatalytic Activities Capable of Accessing Drug-Drug Interaction

2020 ◽  
Author(s):  
Yuan Xu ◽  
Jing Xue ◽  
Qing Zhou ◽  
Yongjun ZHENG ◽  
Xinghua Chen ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Cytochrome P450 ◽  
Drug Interaction ◽  
Cancer Therapy ◽  
Outcome Prediction ◽  
Cost Effective ◽  
Enzyme Mimic ◽  
Drug Dosing ◽  
Drug Drug Interaction ◽  
Biological Context

<p>Emerged as a cost-effective and robust enzyme mimic, nanozymes have drawn increasing attention with broad applications ranging from cancer therapy to biosensing. Developing nanozymes with both accelerated and inhibited biocatalytic properties in a biological context is highly envisioned for perusing more advanced functions of natural enzymes, such as in drug-drug interaction, but remains challenging. By re-visiting the well-known Fe-N-C electrocatalyst that has a heme-like Fe-N<sub>x</sub> coordination active center, herein, we report that the Fe-N-C with a minimum graphitization had an even superior cytochrome P450 (CYP)-like biocatalytic activity. Moreover, the drug metabolization by the Fe-N-C upon co-existence of other foods and drugs demonstrated a trend of inhibition similar to CYP, indicating its great potential as a replacement for <a>drug dosing guide and outcome prediction</a>. Beyond boosting the enzyme-like activity, this work would open a new vista of nanozymes with inhibited behavior for keeping up more demanding applications, enabled by further mimicking the molecular structure of enzymes.</p>

scholarly journals Influences of Corydalis decumbens on the Activities of CYP450 Enzymes in Rats with a Cocktail Approach

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Chen Cheng ◽  
Jianchang Qian ◽  
Zhe Wang ◽  
Wanshu Li ◽  
Chengke Huang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Prescription Drugs ◽  
Complementary Therapy ◽  
Saline Control ◽  
Control Group ◽  
Drug Dosing ◽  
Concurrent Use ◽  
Inductive Effects ◽  
Cocktail Approach

Corydalis decumbens, a Traditional Chinese Medicine, has been widely used for the alternative and/or complementary therapy of hypertension, arrhythmias rheumatoid arthritis, sciatica, stroke, hemiplegia, paraplegia, and vascular embolism. The aim of this study was to determinate the potential effects of Corydalis decumbens on the five cytochrome P450 (CYP) enzyme activities (CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6) by cocktail approach. To evaluate whether concurrent use of Corydalis decumbens interferes with the effect of several prescription drugs, saline (control group) or Corydalis decumbens (XTW group) were administrated via gavage for 7 successive days. A probe cocktail solution (phenacetin, omeprazole, metoprolol, tolbutamide, and midazolam) was given 24 h after the last dose of saline or Corydalis decumbens. A specific and sensitive UHPLC–MS/MS method was validated for the determination of five substrates and their metabolites in control group and XTW group. Our results indicated that Corydalis decumbens could have inductive effects of CYP2C19 and inhibit the activities of CYP1A2 and CYP3A4. However, Corydalis decumbens had no significant influence on CYP2C9 and CYP2D6. The herb-drug interaction should require more attention by careful monitoring and appropriate drug dosing adjustments to the concurrent use of western medications which were metabolized by CYP1A2, CYP2C19, and CYP3A4 in human—Corydalis decumbens, Cytochrome P450, Cocktail, Pharmacokinetics, herb–drug interactions.

Fe-N-C Nanozyme with Both Accelerated and Inhibited Biocatalytic Activities Capable of Accessing Drug-Drug Interaction

2020 ◽  
Author(s):  
Yuan Xu ◽  
Jing Xue ◽  
Qing Zhou ◽  
Yongjun ZHENG ◽  
Xinghua Chen ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Cytochrome P450 ◽  
Drug Interaction ◽  
Cancer Therapy ◽  
Outcome Prediction ◽  
Cost Effective ◽  
Enzyme Mimic ◽  
Drug Dosing ◽  
Drug Drug Interaction ◽  
Biological Context

<p>Emerged as a cost-effective and robust enzyme mimic, nanozymes have drawn increasing attention with broad applications ranging from cancer therapy to biosensing. Developing nanozymes with both accelerated and inhibited biocatalytic properties in a biological context is highly envisioned for perusing more advanced functions of natural enzymes, such as in drug-drug interaction, but remains challenging. By re-visiting the well-known Fe-N-C electrocatalyst that has a heme-like Fe-N<sub>x</sub> coordination active center, herein, we report that the Fe-N-C with a minimum graphitization had an even superior cytochrome P450 (CYP)-like biocatalytic activity. Moreover, the drug metabolization by the Fe-N-C upon co-existence of other foods and drugs demonstrated a trend of inhibition similar to CYP, indicating its great potential as a replacement for <a>drug dosing guide and outcome prediction</a>. Beyond boosting the enzyme-like activity, this work would open a new vista of nanozymes with inhibited behavior for keeping up more demanding applications, enabled by further mimicking the molecular structure of enzymes.</p>

Metabolomics analysis reveals metabolic changes associated with trans-resveratrol treatment in experimental cryptorchidism mice

2021 ◽  
Vol 33 (5) ◽  
pp. 328
Author(s):  
Siqiang Li ◽  
Yun Li ◽  
Fujia Chen ◽  
Yurong Yang ◽  
Li Song ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Immunoblot Analysis ◽  
Untargeted Metabolomics ◽  
Uridine Diphosphate ◽  
Biosynthesis Pathway ◽  
Biochemical Pathways ◽  
Chromatography Tandem Mass Spectrometry ◽  
Hexosamine Biosynthesis ◽  
Liquid Chromatography Tandem Mass ◽  
Hexosamine Biosynthesis Pathway

This study aimed to analyse global metabolomic changes associated with trans-resveratrol (RSV) treatment in mice with cryptorchidism using untargeted metabolomics. Cryptorchidism was established surgically in Kunming mice, which were then treated with 20µg g–1 day–1, s.c., RSV for 35 consecutive days. Typical manifestations of spermatogenesis arrest were seen in mice with cryptorchidism, and RSV treatment for 35 days restored spermatogenesis. Liquid chromatography–tandem mass spectrometry was used to profile the metabolome of testes from mice in the control (non-cryptorchid, untreated), cryptorchid and RSV-treated cryptorchid groups. In all, 1386 and 179 differential metabolites were detected in the positive and negative modes respectively. Seven and six potential biomarkers were screened for spermatogenesis arrest and restoration respectively. Pathway analysis showed changes in 197 metabolic pathways. The hexosamine biosynthesis pathway was inhibited in the cryptorchid group, which probably resulted in a decrease in the end product, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Immunoblot analysis showed that total testicular protein O-linked β-N-acetylglucosamine glycosylation was related to spermatogenesis arrest, further indicating a decrease in UDP-GlcNAc in the cryptorchid group. Thus, untargeted metabolomics revealed the biochemical pathways associated with the restoration of metabolic status in the cryptorchid group following RSV treatment and the findings could be used to monitor the response to RSV treatment. This study provides a meaningful foundation for the future clinical application of RSV in the treatment of spermatogenesis dysfunction.

Molecular evolution of a cytochrome P450 for the synthesis of potential antidepressant (2R,6R)-hydroxynorketamine

2021 ◽  
Author(s):  
Ansgar Bokel ◽  
Michael C. Hutter ◽  
Vlada B. Urlacher
Keyword(s):  
Cytochrome P450 ◽  
Molecular Evolution ◽  
Cytochrome P450 Monooxygenase ◽  
P450 Monooxygenase ◽  
Effective Synthesis

Engineered cytochrome P450 monooxygenase CYP154E1 enables the effective synthesis of the potential antidepressant (2R,6R)-hydroxynorketamine via N-demethylation and regio- and stereoselective hydroxylation of (R)-ketamine.

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