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Next-Generation Immunoassays
Published in Richard O’Kennedy, Caroline Murphy, Immunoassays, 2017
Valerie Fitzgerald, Paul Leonard
Nanosphere have developed their Verigene platform based on the use of gold nanoparticles as secondary labels, which are then enlarged by catalytic silver deposition until they can be imaged using a regular slide scanner or conventional camera [30]. Depending upon the application, each nanoparticle is functionalized with either a defined number of oligonucleotides (i.e. short pieces of DNA or RNA with sequences complementary to target sequences of clinical interest) or a defined number of antibodies that are specific to a particular protein of interest (e.g. prostate-specific antigen (PSA) [67] and cardiac troponin I (cTnI)). Whole blood is dropped in a disposable cartridge which contains all required reagents for sample preparation, nanoparticle labelling and silver deposition. The processing is completely automated and results are read using a slide scanner. The complete test takes only 90 minutes. Verigene platforms are available for application in areas of infectious diseases (e.g. gram-positive and negative blood culture, enteric pathogens and for respiratory viruses such as influenza), pharmacogenetics (e.g. drug-metabolizing enzyme CYP2C19), cardiology (e.g. cTnI) and human genetics (e.g. the F5 gene can be implicated in deep vein thrombosis). Additional information about the platform is available from http://www.nanosphere.us/.
Precision Medicine
Published in Paul Cerrato, John Halamka, Reinventing Clinical Decision Support, 2020
Within this series of hepatic enzymes, Medicare coverage is only provided for CYP2D6 testing for patients who are starting treatment on the antidepressants amitriptyline or nortriptyline, and for anyone taking tetrabenazine in doses above 50 mg/day. The agency will also cover CYP2C19 testing for patients starting or restarting clopidogrel, but only if they have acute coronary syndrome and are undergoing percutaneous coronary intervention (PCI).12
Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sanjana Haque, Yuqing Gong, Sunitha Kodidela, Mohammad A. Rahman, Sabina Ranjit, Santosh Kumar
According to recent FDA guidelines, if >10% of a parent drug forms a metabolite, that metabolite will need to undergo separate toxicity testing. For this purpose, large quantities of the drug metabolite is needed (FDA, 2016). Therefore, recent studies highlighted the broad applications of engineered CYPBM3 in the production of human metabolites (Girvan and Munro, 2016). For example, the Munro group engineered CYPBM3 by rational mutagenesis to facilitate the binding of the proton pump inhibitor, omeprazole. The mutations of F87V and A82F resulted in a conformational alternation and a decreased free energy barrier, ultimately changing the substrate recognition. These mutants of CYPBM3 were able to transform omeprazole to the human CYP2C19-type metabolite (Butler et al., 2013). The same group further demonstrated the efficient transformation of several proton pump inhibitors (e.g., lansoprazole, esomeprazole) to human CYP-type metabolites by CYPBM3 F87V/A82F mutants (Butler et al., 2014). In a recent work, a library of CYPBM3 variants carrying multiple mutations that were identified from directed evolutions showed a high oxidation activity for a wide range of drugs. Few of these drugs include, non-steroidal anti-inflammatory drugs/NSAIDs (diclofenac and naproxen), muscle relaxant (chlorzoxazone), antidepressant (amitriptyline), anesthetic, antiarrhythmic drug (lidocaine), and steroid hormones (testosterone). Importantly, CYPBM3 mutants from this library converted diclofenac with 91–100% conversion, and produced human CYP2C9-type and CYP3A4-type metabolites, 4’-hydroxylated and 5’-hydroxylated diclofenac with 34% yield and 47% yield, respectively (Ren et al., 2015). In another recent example, CYPBM3 mutant M11, has been proven to produce human metabolites of fenamic acid NSAIDs including mefenamic acid, meclofenamic acid, and tolfenamic acid (Venkataraman et al., 2014; Capoferri et al., 2016). Mutant M11 was generated by using random mutagenesis and had 90-fold higher initial activities compared with human CYP2D6 (van Vugt-Lussenburg et al., 2007). This mutant was able to synthesize benzylic or aromatic hydroxylation metabolites of the fenamic acid NSAIDs with high substrate conversions and high turnover numbers (2000–6000). Because of the high total turnover numbers, M11 can be used as a biocatalytic tool for large-scale production of fenamic acid metabolites to perform characterization study, activity study, and toxicological evaluation of NSAIDs (Venkataraman et al., 2014). Similarly, mutant M11 was capable of metabolizing anticancer drugs cyclophosphamide and ifosfamide, producing active metabolites. It can also be used for extracellular bioactivation, and for providing a catalytically efficient alternative to liver S9 fraction for toxicity evaluation (Vredenburg et al., 2015). In addition, a set of BM3 mutants, generated using both rational and random mutagenesis, was able to produce human metabolites of 17β-estradiol. This engineered CYPBM3 enzyme can catalyze same reactions as human CYP1A1, CYP1A2, and CYP1B1 with high catalytic efficiency (kcat/Km) and total turnover numbers between 1040 and 1210, producing human metabolites for industrial applications (Cha et al., 2014).
Cecropia pachystachya Trécul: identification, isolation of secondary metabolites, in silico study of toxicological evaluation and interaction with the enzymes 5-LOX and α-1-antitrypsin
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Penina Sousa Mourão, Rafael de Oliveira Gomes, Clara Andrezza Crisóstomo Bezerra Costa, Orlando Francisco da Silva Moura, Herbert Gonzaga Sousa, George Roberto Lemos Martins Júnior, Danniel Cabral Leão Ferreira, Antônio Luiz Martins Maia Filho, Johnnatan Duarte de Freitas, Mahendra Rai, Francisco Das Chagas Alves Lima, Antonio Euzébio Gourlart Santana, Mariana Helena Chaves, Wellington Dos Santos Alves, Valdiléia Teixeira Uchôa
CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are important enzymes in drug interactions and belong to the cytochrome P450 enzyme family, which is a family of monooxygenases involved in drug metabolism and responsible for metabolism of xenobiotics (Braz et al. 2018; Silva, da Silva, and Holanda 2020; Silvado 2008). Inhibition of these enzymes may trigger unwanted effects such as drug accumulation and or increased toxicity of the drug affected by the interaction, or reduced effectiveness (Braz et al. 2018). The last prediction analyzed here in PreADMET results is the similarity of bioactive compounds to a drug, which can be described by Lipinski´s Rule (also known as Lipinski´s Rule 5) which establishes molecular parameters to determine if molecules display reliable potential to become a new drug (Gomes and Leite 2021).
Pharmacokinetics of α-amanitin in mice using liquid chromatography-high resolution mass spectrometry and in vitro drug–drug interaction potentials
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Ria Park, Won-Gu Choi, Min Seo Lee, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang, Chang Hwan Sohn, Im-Sook Song, Hye Suk Lee
The inhibition potential of α-amanitin against the eight major CYP and six major UGT enzymes was evaluated in HLMs. α-Amanitin weakly inhibited CYP2A6-catalyzed coumarin 7′-hydroxylation (IC50, 49.3 μM), CYP2B6-catalyzed bupropion hydroxylation (IC50, 52.7 μM), CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation (IC50, 68.8 μM), CYP2D6-catalyzed bufuralol 1′-hydroxylation (IC50, 56.9 μM), and CYP3A4-catalyzed midazolam 1′-hydroxylation (IC50, 91.1 μM) in HLMs. α-Amanitin showed negligible inhibition of CYP1A2-catalyzed phenacetin O-deethylation, CYP2C8-catalyzed amodiaquine N-deethylation, and CYP2C9-catalyzed diclofenac 4′-hydroxylation upto100 μM α-amanitin in HLMs (Figure 4). There was no time-dependent inhibition of α-amanitin on 8 CYPs after 30-min preincubation (Figure 4, Table 8).
Modulating effect of DL-kavain on the mutagenicity and carcinogenicity induced by doxorubicin in Drosophila melanogaster
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Thaís Teixeira da Silva, Júlia Braga Martins, Maria Do Socorro de Brito Lopes, Pedro Marcos de Almeida, José Luiz Silva Sá, Francielle Alline Martins
Kavalactones, individually or combined with methanolic kava extract, were reported to inhibit a number of cytochrome 450 (CYP450) isoforms, including CYP1A2, CYP2C9; CYP2C19; CYP2D6, CYP3A4; CYP4A9 and CYP4A9/11 (Mathews, Etheridge, and Black 2002; Mathews et al. 2005). This property is the source of numerous interactions, primarily pharmacokinetic, with other drugs, since kavalactones and kava extract decrease metabolism by blocking enzymes of the CYP450 complex, thereby inducing toxicity (Mathews, Etheridge, and Black 2002; Zou et al. 2004). The bioactivation and biotransformation pathways of kavain were reported in mice by Wang et al. (2019) who identified 28 metabolites in liver, urine and feces. CYP2C19, one of the CYP450 enzymes, was the major enzyme contributing to biotransformation and bioactivation of kavain. Although pharmacokinetic and/or pharmacodynamic studies have advanced knowledge over the years, only in vitro few studies were conducted to investigate the toxicogenetic potential of kavain and other kavalactones (Celentano et al. 2020; Li et al. 2012; Shaik, Hermanson, and Xing 2009; Zi and Simoneau 2005).