Association between &lt;i&gt;in vitro&lt;/i&gt; nuclear receptor-activating profiles of chemical compounds and their &lt;i&gt;in vivo&lt;/i&gt; hepatotoxicity in rats

Kodama, Susumu; Yoshii, Nao; Ota, Akinobu; Takeshita, Jun-ichi; Yoshinari, Kouichi; Ono, Atsushi

doi:10.2131/jts.46.569

Cited by 3 publications

(2 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many of these proteins play crucial roles in blood coagulation and calcium regulation within the bone and vasculature (Figure 3). Examples of extensively studied hepatic Gla proteins include Factor II (prothrombin), Factor VII, Factor IX, Factor X, Protein S, and Protein C. The liver is the main site for the synthesis of these proteins, contributing to the precise spatiotemporal control of the blood clotting cascade [32,[43][44][45]. Specifically, the gamma-carboxylation ensures effective assembly and disassembly of the tenase complex by facilitating calcium and phospholipid binding.…”

Section: Gla Proteins and Human Healthmentioning

confidence: 99%

“…Examples of extrahepatic Gla proteins include osteocalcin (involved in bone metabolism) and matrix Gla-protein (MGP, involved in the regulation of vascular calcification) [40,41,47]. MK-4 is crucial for the gamma-carboxylation of these proteins, allowing them to bind calcium ions and perform their respective functions in tissues outside the liver [44].…”

Section: Key Forms and Sources Of Vitamin Kmentioning

confidence: 99%

See 1 more Smart Citation

Pregnane X Receptor Signaling Pathway and Vitamin K: Molecular Mechanisms and Clinical Relevance in Human Health

Staudinger,

Mahroke,

Patel

et al. 2024

Cells

View full text Add to dashboard Cite

This review explores the likely clinical impact of Pregnane X Receptor (PXR) activation by vitamin K on human health. PXR, initially recognized as a master regulator of xenobiotic metabolism in liver, emerges as a key regulator influencing intestinal homeostasis, inflammation, oxidative stress, and autophagy. The activation of PXR by vitamin K highlights its role as a potent endogenous and local agonist with diverse clinical implications. Recent research suggests that the vitamin K-mediated activation of PXR highlights this vitamin’s potential in addressing pathophysiological conditions by promoting hepatic detoxification, fortifying gut barrier integrity, and controlling pro-inflammatory and apoptotic pathways. PXR activation by vitamin K provides an intricate association with cancer cell survival, particularly in colorectal and liver cancers, to provide new insights into potential novel therapeutic strategies. Understanding the clinical implications of PXR activation by vitamin K bridges molecular mechanisms with health outcomes, further offering personalized therapeutic approaches for complex diseases.

show abstract

Section: Gla Proteins and Human Healthmentioning

confidence: 99%

Section: Key Forms and Sources Of Vitamin Kmentioning

confidence: 99%

Pregnane X Receptor Signaling Pathway and Vitamin K: Molecular Mechanisms and Clinical Relevance in Human Health

Staudinger,

Mahroke,

Patel

et al. 2024

Cells

View full text Add to dashboard Cite

show abstract

Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha

et al. 2023

View full text Add to dashboard Cite

Machine Learning-Based In Silico Prediction of the Inhibitory Activity of Chemical Substances Against Rat and Human Cytochrome P450s

Ambe,

Nakamori,

Tohno

et al. 2024

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The prediction of cytochrome P450 inhibition by a computational (quantitative) structure−activity relationship approach using chemical structure information and machine learning would be useful for toxicity research as a simple and rapid in silico tool. However, there are few in silico models focusing on the species differences between rat and human in the P450s inhibition. This study aimed to establish in silico models to classify chemical substances as inhibitors or noninhibitors of various rat and human P450s, using only molecular descriptors. Using the in-house test results from our in vitro experiments, we used 326 substances for model construction and internal validation data. Apart from the 326 substances, 60 substances were used as external validation data set. We focused on seven rat P450s (CYP1A1, CYP1A2, CYP2B1, CYP2C6, CYP2D1, CYP2E1, and CYP3A2) and 11 human P450s (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Most of the models established using XGBoost showed an area under the receiver operating characteristic curve (ROC-AUC) of 0.8 or more in the internal validation. When we set an applicability domain for the models and confirmed their generalization performance through external validation, most of the models showed an ROC-AUC of 0.7 or more. Interestingly, for CYP1A1 and CYP1A2, we discovered that a human P450 inhibitory activity model can predict rat P450 inhibitory activity and vice versa. These models are the first attempts to predict inhibitory activity against a wide variety of P450s in both rats and humans using chemical structure information. Our experimental results and in silico models would be helpful to support information for species similarities and differences in chemical-induced toxicity.

show abstract

Association between <i>in vitro</i> nuclear receptor-activating profiles of chemical compounds and their <i>in vivo</i> hepatotoxicity in rats

Cited by 3 publications

References 56 publications

Pregnane X Receptor Signaling Pathway and Vitamin K: Molecular Mechanisms and Clinical Relevance in Human Health

Pregnane X Receptor Signaling Pathway and Vitamin K: Molecular Mechanisms and Clinical Relevance in Human Health

Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha

Machine Learning-Based In Silico Prediction of the Inhibitory Activity of Chemical Substances Against Rat and Human Cytochrome P450s

Contact Info

Product

Resources

About