Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole          Fungicides: an Application of the Fused-grid Template* system

Yamazoe, Yasushi; Yamada, Takashi; Nagata, Kiyoshi

doi:10.14252/foodsafetyfscj.d-20-00010

Cited by 14 publications

(6 citation statements)

References 48 publications

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“…1 D, 2 G and 3 D). The results obtained in the present and previous studies 1 , 2 , 8 , 9 ) suggest our CYP Template systems as effective tools to warn an appearance of unstable reactive intermediates. Our CYP-Template systems would support confident judgements in safety assessments through offering the mechanistic understandings of the metabolism.…”

Section: Discussionsupporting

confidence: 77%

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Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

2022

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Cytochrome P450 (CYP)-mediated metabolisms of four chemicals have been investigated to understand their unresolved phenomena of their metabolisms using human CYP-Template systems developed in our previous studies (Drug Metab Pharmacokinet 2019, 2021, 2022). Simulation experiments of a topoisomerase-targeting agent, amonafide, offered a possible new inhibitory-mechanism as Trigger-residue inactivation on human CYP1A2 Template. N -Acetylamonafide as well as amonafide would inactivate CYP1A2 through the interference of Trigger-residue movement with their dimethylaminoethyl parts. The mechanism was also supported on the inhibition/inactivation of two other drugs, DSP-1053 and binimetinib. Both the drugs, after other CYP-mediated slight structural alterations, were expected to interact with Trigger-residue for the intense inhibition on CYP1A2 Template. Possible formation of reactive intermediates of amonafide and 3-methylindole was also examined on CYP1A2 Template. Placements of amonafide suggested the scare N -oxidation of the arylamine part due to the Trigger-residue interaction. Placements of 3-methylindole suggested the formation of a reactive intermediate, 3-methyleneindolenine, rather selectively on rodent CYP1A2 than on human CYP1A2, in consistent with the experimental data. These results suggest that CYP Template systems developed are effective tools to warn an appearance of unstable reactive intermediates. Our CYP-Template systems would support confident judgements in safety assessments through offering the mechanistic understandings of the metabolism.

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Section: Discussionsupporting

confidence: 77%

“…Placements of ligands on Template systems of human CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3As offered the information on sites of metabolisms regio- and stereo-selectively with more than 99% of accuracies. These Template systems are shown as effective tools for drug metabolism prediction and safety assessment 8 , 9 , 10 ) .…”

Section: Introductionmentioning

confidence: 99%

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

2022

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“…Chem3D (version 5 for Mac OS, CambridgeSoft, Cambridge, MA) and ChemBio3D (version 12 for Windows, CambridgeSoft) and ChemBioDraw (versions 11 and 13 for Mac OS, CambridgeSoft/PerkinElmer) were used to construct two-dimentional (2D) or three-dimensional (3D) structures of the substrates and to overlay compounds on Template. Several template-terms are defined to explain ligand interactions with Template in our previous studies 10 , 11 , 12 , 13 , 14 , 15 ) . These terms are listed in a separate section as “Template terms used”.…”

Section: Methodsmentioning

confidence: 99%

“…Cavity-2 residue descended would immobilize ligands to trigger the catalyses in the Template system. Other experimental details of CYP3A4, CYP3A5 and CYP3A7 Template systems are described in our publications 10 , 11 , 12 , 13 , 14 , 15 ) .…”

Section: Methodsmentioning

confidence: 99%

Deciphering Key Interactions of Ligands with CYP3A4-Template* system

et al. 2021

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Cytochrome P450 (CYP)-mediated metabolisms are often associated with biological and toxicological events of chemicals. A major hepatic enzyme, CYP3A4, showed clear distinctions on their catalyses even among ligands having resemble structures. To better understand mechanisms of their distinct catalyses, possible associations of ligand interactions at specific parts of CYP3A4 residues were investigated using CYP3A4-Template system developed (DMPK 2019 and 2020). A placement was available selectively for CYP3A4-mediated R-thalidomide 5-oxidation on Template, but not for the 5'-oxidation and the S-isomer oxidations. Similar placements were generated for pomalidomide (4-amino-thalidomide), but not for a poor ligand, lenalidomide (3-deoxy-pomalidomide). The latter ligand took placements lacking IJK-Interaction or sticking the 4-amino part beyond the facial-side wall on Template. A placement was available for the tert-butyl oxidation of terfenadine, but not for an analog, ebastine. Their interactions with upper-Cavity-2 residue were expected to differ at their sites of oxygen substituents. Some phenolic antioxidants behave distinctly toward biological oxidations in vitro and in vivo. Butylated hydroxytoluene is oxidized to the peroxy-derivative in vitro, but solely to the oxidized metabolites at the benzyl and tert-butyl methyl positions in vivo. Involvement of CYP3A4 were suggested for all the three reactions from the placements on Template. Tocopherols were also applied on Template for the oxidations for chroman and side-chain terminals. The primary placement was suggested to undergo the futile-recycling through formation of the peroxide intermediate subsequently to lead the substantial lack of the CYP3A4-mediated oxidation. These data suggest the effectiveness of CYP3A4-Template assessment to understand the causal basis of poor oxidations and also to verify the in vivo contribution of CYP3A4-mediated peroxidative reactions.

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“…Placements of ligands on Template systems of human CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3As offered the information on sites of metabolisms regio- and stereo-selectively with more than 99% of accuracies. These Template systems are shown as effective tools for drug metabolism prediction and safety assessment [ 14 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms

et al. 2023

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Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of β-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, β-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.

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Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system

Cited by 14 publications

References 48 publications

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

Deciphering Key Interactions of Ligands with CYP3A4-Template* system

Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms

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