Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 50, 2020 - Issue 6
274
Views
1
CrossRef citations to date
0
Altmetric
General Xenobiochemistry

Evaluation of mRNA expression of drug-metabolizing enzymes in acetaminophen-induced hepatotoxicity using a three-dimensional hepatocyte culture system

, , , , &
Pages 654-662 | Received 26 Aug 2019, Accepted 17 Oct 2019, Published online: 05 Nov 2019
 

Abstract

1. The expression and activity of drug-metabolizing enzymes are known to affect the pharmacokinetics of drugs metabolized in the liver. Here, we assessed the effect of acetaminophen (APAP)-induced hepatotoxicity on the mRNA expression of drug-metabolizing enzymes and elucidated the underlying mechanism using three-dimensional (3D) cultures of HepG2 cells.

2. 3D culture cells enabled us to establish an in vitro model of APAP-induced hepatotoxicity which showed the increase in N-acetyl-p-benzoquinone imine production, reactive oxygen species (ROS) generation and cellular injury.

3. In this 3D culture model, APAP treatment significantly increased the mRNA expression of drug-metabolizing enzymes (cytochrome P450 [CYP]3A4, CYP2E1 and UDP-glucuronosyltransferase 1A6) and their nuclear receptors (pregnane X receptor and constitutive androstane receptor) compared with untreated cells. Treatment with N-acetylcysteine, a therapeutic agent for APAP-induced hepatotoxicity, suppressed these increases. In addition, the mRNA expression of drug-metabolizing enzymes and nuclear receptors were elevated depending on the concentration of H2O2, one of ROS involved in the development of APAP-induced hepatotoxicity. The mRNA expression of nuclear receptors increased before that of drug-metabolizing enzymes.

4. In conclusion, ROS may induce the mRNA expression of nuclear receptors and promote the transcription of drug-metabolizing enzymes in the in vitro model of APAP-induced hepatotoxicity.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by JSPS KAKENHI Grant Number 16K18947.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.