Development of a strategy to identify and evaluate direct and indirect activators of constitutive androstane receptor in rats
Copyright © 2022 Elsevier Ltd. All rights reserved..
Constitutive androstane receptor (CAR) is a nuclear receptor that plays a key role in drug metabolism and disposition and in the development of liver tumors in rodents. CAR is activated by ligands and indirect activators, which do not bind to the receptor but activate it through cellular signaling. In this study, we sought to identify direct and indirect activators of rat CAR (rCAR). Assessment of the influence of mutations on the transcriptional activity of rCAR identified a mutant termed rCAR-3A-G354Q that displays low constitutive activity and high ligand responsiveness. Reporter assays using the mutant were performed with compounds that increased the mRNA levels of Cyp2b1, a CAR target gene, in rat primary hepatocytes. Several compounds activated rCAR-3A-G354Q and were implicated as rCAR ligands. Since indirect CAR activators are considered to display little species differences, we then determined CYP2B6 mRNA levels in human hepatocyte-like HepaRG cells after treatment with compounds that increased Cyp2b1 mRNA levels in rat hepatocytes but did not activate rCAR-3A-G354Q. The results demonstrated six compounds as possible rCAR indirect activators. Taken together, the combined measurement of Cyp2b1 mRNA levels in rat primary hepatocytes and rCAR-3A-G354Q activation in reporter assays can be useful for evaluating rCAR activation by chemicals.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:170 |
|---|---|
| Enthalten in: |
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association - 170(2022) vom: 15. Dez., Seite 113510 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sato, Takumi [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 06.12.2022 Date Revised 06.12.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.fct.2022.113510 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM348704259 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM348704259 | ||
| 003 | DE-627 | ||
| 005 | 20231226040902.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.fct.2022.113510 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1162.xml |
| 035 | |a (DE-627)NLM348704259 | ||
| 035 | |a (NLM)36356836 | ||
| 035 | |a (PII)S0278-6915(22)00708-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sato, Takumi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Development of a strategy to identify and evaluate direct and indirect activators of constitutive androstane receptor in rats |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.12.2022 | ||
| 500 | |a Date Revised 06.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Constitutive androstane receptor (CAR) is a nuclear receptor that plays a key role in drug metabolism and disposition and in the development of liver tumors in rodents. CAR is activated by ligands and indirect activators, which do not bind to the receptor but activate it through cellular signaling. In this study, we sought to identify direct and indirect activators of rat CAR (rCAR). Assessment of the influence of mutations on the transcriptional activity of rCAR identified a mutant termed rCAR-3A-G354Q that displays low constitutive activity and high ligand responsiveness. Reporter assays using the mutant were performed with compounds that increased the mRNA levels of Cyp2b1, a CAR target gene, in rat primary hepatocytes. Several compounds activated rCAR-3A-G354Q and were implicated as rCAR ligands. Since indirect CAR activators are considered to display little species differences, we then determined CYP2B6 mRNA levels in human hepatocyte-like HepaRG cells after treatment with compounds that increased Cyp2b1 mRNA levels in rat hepatocytes but did not activate rCAR-3A-G354Q. The results demonstrated six compounds as possible rCAR indirect activators. Taken together, the combined measurement of Cyp2b1 mRNA levels in rat primary hepatocytes and rCAR-3A-G354Q activation in reporter assays can be useful for evaluating rCAR activation by chemicals | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Constitutive androstane receptor | |
| 650 | 4 | |a Drug-metabolizing enzyme | |
| 650 | 4 | |a Hepatocarcinogenesis | |
| 650 | 4 | |a Ligands | |
| 650 | 4 | |a Primary hepatocyte | |
| 650 | 4 | |a Reporter assay | |
| 650 | 7 | |a Constitutive Androstane Receptor |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP2B1 |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a Receptors, Cytoplasmic and Nuclear |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 700 | 1 | |a Shizu, Ryota |e verfasserin |4 aut | |
| 700 | 1 | |a Miura, Yoshie |e verfasserin |4 aut | |
| 700 | 1 | |a Hosaka, Takuomi |e verfasserin |4 aut | |
| 700 | 1 | |a Kanno, Yuichiro |e verfasserin |4 aut | |
| 700 | 1 | |a Sasaki, Takamitsu |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshinari, Kouichi |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association |d 1982 |g 170(2022) vom: 15. Dez., Seite 113510 |w (DE-627)NLM012624691 |x 1873-6351 |7 nnns |
| 773 | 1 | 8 | |g volume:170 |g year:2022 |g day:15 |g month:12 |g pages:113510 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.fct.2022.113510 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 170 |j 2022 |b 15 |c 12 |h 113510 | ||