Construction of a CYP2J2-Template System and Its Application for Ligand Metabolism Prediction.

A Template system for the understanding of human CYP2J2-mediated reactions was constructed from the assembly of the ligands with the introduction of ideas of allowable width, Trigger-residue and the residue-initiated movement of ligands in the active site, which were in common with other Template* systems for human CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP3A4, CYP3A5, and CYP3A7 (Drug Metab Pharmacokinet 2016, 2017, 2019, 2020, 2021, 2022, 2023, 2024, and in press 2024). CYP2J2 system also includes ideas of bi-molecule binding of ligands on the Template. From their placements on the Template and rules for interaction modes, verifications of good and poor substrates, regio/stereo-selectivity, and inhibitory interaction became available faithfully for these ligands.

Erratum: Retraction Notice.

[This corrects the article DOI: 10.14252/foodsafetyfscj.D-21-00006.

Construction of a fused grid-based CYP2C18-Template system and its application to drug metabolism.

Detailed estimation of cytochrome P450 (CYP)-mediated metabolisms of medicine and other chemicals is necessary for the efficacy and safety assessments. Data on the metabolisms mediated by minor CYP enzymes like CYP2C18 are often not available in metabolisms and safety assessments of chemicals except for medical drugs developed recently. A ligand-accessible space in the active site of human CYP2C18 was thus reconstituted as a fused grid-based Template with the use of structural data of its ligands.

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

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.

Construction of a fused grid-based CYP2C19-Template system and the application.

A ligand-accessible space in the CYP2C19 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. An evaluation system of CYP2C19-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C19 and its ligands through the simultaneous plural-contact with Rear-wall of Template.

Construction of a fused grid-based CYP2C8-Template system and the application.

A ligand-accessible space in the CYP2C8 active site was reconstituted as a fused grid-based Template∗ with the use of structural data of the ligands. An evaluation system of CYP2C8-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C8 and its ligands through the simultaneous plural-contact with Rear-wall of Template.

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

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. -Acetylamonafide as well as amonafide would inactivate CYP1A2 through the interference of Trigger-residue movement with their dimethylaminoethyl parts.

Combined Risk Assessment of Food-derived Coumarin with Approaches.

Hepatotoxicity associated with food-derived coumarin occurs occasionally in humans. We have, herein, assessed the data of existing clinical and nonclinical studies as well as those of models for humans in order to shed more light on this association. The average intakes of food-derived coumarin are estimated to be 1-3 mg/day, while a ten-times higher level is expected in the worst-case scenarios.

Construction of a fused grid-based template system of CYP2C9 and its application.

A ligand-accessible space in the CYP2C9 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. CYP2C9 Template generated has been developed as an evaluation system of CYP2C9 metabolism with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C9 and its ligands through the simultaneous plural-contact with Rear-wall of Template.

Refined CYP2E1 Template system to decipher the ligand-interactions.

A Template system for a prediction of human CYP2E1-mediated reactions (Drug Metab Rev 2011) has been refined with the introduction of ideas of Trigger-residue and the residue-initiated movement of ligands in the active site. The refined system also includes ideas of bi-molecule binding and angled-placement, which allow to sit diverse types of ligands on Template. With the use of these ideas in common with other Template systems for human CYP1A1, CYP1A2 and CYP3A4 (Drug Metab Pharmacokinet 2016, 2017, 2019, and 2020), 349 reactions of 192 distinct chemicals published as CYP2E1 ligands were examined in the refined system.

Development of template systems for ligand interactions of CYP3A5 and CYP3A7 and their distinctions from CYP3A4 template.

Starting from established CYP3A4 Template (DMPK. 2019, and 2020), CYP3A5 and CYP3A7 Templates have been constructed to be reliable tools for verification of their distinct catalytic properties. A distinct occupancy was observed on CYP3A4-selective ligands, but not on the non-selective ligands, in simulation experiments.

Deciphering Key Interactions of Ligands with CYP3A4-Template* system.

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).

Applications of a grid-based CYP3A4 Template system to understand the interacting mechanisms of large-size ligands; part 4 of CYP3A4 Template study.

Catalytic interactions of CYP3A4 with large-size ligands have been studied on the Template established in our previous studies using polyaromatic hydrocarbon and steroid ligands (DMPK 34: 113-125 and 351-364 2019 and in press 2020). Typical CYP3A4-substrates including erythromycin, cyclosporin A (ca.1200 Da), ivermectin B1a and taxanes were applied successfully and regioselective metabolisms of these ligands were reconstituted faithfully on Template.

Antiepileptic Drug-Activated Constitutive Androstane Receptor Inhibits Peroxisome Proliferator-Activated Receptor and Peroxisome Proliferator-Activated Receptor Coactivator 1-Dependent Gene Expression to Increase Blood Triglyceride Levels.

Long-term administration of some antiepileptic drugs often increases blood lipid levels. In this study, we investigated its molecular mechanism by focusing on the nuclear receptors constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR), which are key transcription factors for enzyme induction and lipid metabolism, respectively, in the liver. Treatment of mice with the CAR activator phenobarbital, an antiepileptic drug, increased plasma triglyceride levels and decreased the hepatic expression of PPAR target genes related to lipid metabolism.

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

Human CYP3A4 is involved in metabolisms of diverse hydrophobic chemicals. Using the data of therapeutic azole fungicides known to interact with CYP3A4, applicability of CYP3A4 Template system was first confirmed to reconstitute faithfully the interaction on Template. More than twenty numbers of pesticide azoles were then applied to the Template system.

Versatile applicability of a grid-based CYP3A4 Template to understand the interacting mechanisms with the small-size ligands; part 3 of CYP3A4 Template study.

Modes of interactions of small ligands with CYP3A4 have been defined using the Template established in our previous studies (DMPK. 34: 113-125 2019 and 34 351-364 2019). Interactions of polyaromatic hydrocarbons such as benzo[a]pyrene, pyrene and dibenzo[a,j]acridine were refined with the idea of Right-side movement of ligands at Rings A and B of Template.

A Summary Report of FSCJ Workshop "Future Challenges and Opportunities in Developing Methodologies for Improved Human Risk Assessments".

This is a summary report of FSCJ (Food Safety Commission of Japan) workshop entitled "Future Challenges and Opportunities in Developing Methodologies for Improved Human Risk Assessments, which held in November 2018. Scientific advancements have facilitated the development of new methods for chemical risk assessments with the expansion of toxicological databases. They are promising tools to overcome challenges, such as situations of data insufficiency, estimation of internal exposure and prediction of hazard, and enable us to improve our human health risk assessment in food safety.

Prediction of regioselectivity and preferred order of CYP1A1-mediated metabolism: Solving the interaction of human and rat CYP1A1 forms with ligands on the template system.

A simulation system for ligand interaction of human CYP1A1 has been developed using "Template" composed of hexagonal grids, as a modification of CYP1A2 system established previously. Differing from CYP1A2 Template, Site of Oxidation of CYP1A1 was located one-grid (Ring) away horizontally from Trigger-Region (Ring B) on CYP1A1 Template. Simultaneous interaction at Site of Oxidation and Trigger-Region as uni- or bi-molecule binding was maintained with CYP1A1 as well as CYP1A2 for the functional contributions.

UDP-Glucuronosyltransferase (UGT)-mediated attenuations of cytochrome P450 3A4 activity: UGT isoform-dependent mechanism of suppression.

Background And Purpose: Cytochrome P450 (CYP, P450) 3A4 is involved in the metabolism of 50% of drugs and its catalytic activity in vivo is not explained only by hepatic expression levels. We previously demonstrated that UDP-glucuronosyltransferase (UGT) 2B7 suppressed CYP3A4 activity through an interaction. In the present study, we target UGT1A9 as another candidate modulator of CYP3A4.

Solving the interactions of steroidal ligands with CYP3A4 using a grid-base template system.

Using over fifty steroidal ligands, CYP3A4 Template system established in our previous study (DMPK 34: 113-125, 2019) has been evaluated for the applicability for prediction of regioselective metabolisms of steroids in the present study. Plural regional interactions near Site of Oxidation of CYP3A4 (Slide-down and Adaptation) are newly defined for steroid ligands in addition to previously characterized Trigger- and IJL-interactions on Template. Interaction of steroids at ring-A with CYP3A4 residue (Front-residue), at the facial side of Ring B of Template, determined the availability of ligand sitting at Rings A and B of Template.

Prediction of regioselectivity and preferred order of metabolisms on CYP1A2-mediated reactions part 3: Difference in substrate specificity of human and rodent CYP1A2 and the refinement of predicting system.

Differences in CYP1A2-mediated metabolisms in human, rat and mouse have been analyzed with Template of human CYP1A2 established in our previous studies (Drug Metab Pharmacokinet 31:363, 2016 and 32:229, 2017). Using more than 25 chemicals including phenanthrene, MeIQx, PhIP, caffeine and furafylline, Template for human CYP1A2 was found to be applicable for rat and mouse CYP1A2 reactions with the consideration of five distinct regional interactions: 1) Expanded use of Ring D region of pro-metabolized molecules and also of trigger molecules, 2) acceptance of secondary amino groups at Position 31 of Ring eC1, 3) overlapping of pro-metabolized and trigger molecules at Ring eC4, 4) restricted maneuvering of substrates into Bay 1 region, and 5) allowance of passage of slightly large ligands in Thin-Area. These distinction points were found to be mutual for both substrates and inhibitors.

Reconstitution of CYP3A4 active site through assembly of ligand interactions as a grid-template: Solving the modes of the metabolism and inhibition.

A hexagonal-grid based template system has been developed to a predicting tool of CYP3A4-mediated reactions through the reconstitution of the active site with the assembly of the ligands. Simultaneous interactions of flattened-shape ligands at two sites of CYP3A4, oxidizing- and triggering-sites, are essential ideas, which were supported in the simulation results of various ligands on the template. The interactions were accomplished with either uni-molecule bindings or bi-molecule bindings with ligands termed pro-metabolized and trigger molecules.

Possible Role of Phosphatidylcholine and Sphingomyelin on Fumonisin B1-mediated Toxicity.

A major corn-related mycotoxin, fumonisin B1 (FB1), continues to attract attention of researchers as well as risk-assessors due to the diverse toxicological characteristics, including distinct target tissues in different animal species and opposite susceptibility in males and females in mice and rats. More than thirty years passed since the structure identification as a sphingoid-like chemical, but the causal mechanism of the toxicity remains obscure in spites of extensive studies. Considerable amounts of knowledge have been accumulated on the biochemical/toxicological actions of FB1, but the influence on lipid dynamics and mobilization in the body has not been focused well in relation to the FB1-mediated toxicity.