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Open AccessArticle

Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells

1
Toxicology Laboratory, Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul 05029, Korea
2
R & D department, Morningbio Co., Ltd., Cheonan 31111, Korea
*
Author to whom correspondence should be addressed.
Received: 12 November 2019 / Revised: 15 December 2019 / Accepted: 17 December 2019 / Published: 18 December 2019
(This article belongs to the Section Mycotoxins)
Zearalenone (ZEN) is a mycotoxin produced by Fusarium species; however, its mechanisms of action in human livers have not been fully elucidated. Thus, we investigated the toxic mechanisms of ZEN in human liver cells. HepG2 cells were treated with ZEN (0–40 μg/mL) for up to 24 h. A significant decrease in cell viability was observed after treatment with 20 and 40 μg/mL of ZEN, including a significant increase in apoptosis and reactive oxygen species production. ZEN increased GRP78 and CHOP, and eIF2α phosphorylation, indicating ER stress; elevated transcription of the autophagy-associated genes, beclin1 and LC3, and translation of LC3; and increased phase I metabolism by increasing PXR and CYP3A4. The protein expression level of CYP3A4 was higher with ZEN treatment up to 20 μg/mL, but remained at the control level after treatment with 40 μg/mL ZEN. In phase II metabolism, Nrf2 activation and UGT1A expression were increased with ZEN treatment up to 20 μg/mL. Treating cells with an ER stress inhibitor alleviated ZEN-induced cell death and autophagy, and inhibited the expression of phase I/II enzymes. Overall, high ZEN concentrations can modulate the expression of phase I/II enzymes via ER stress and reduced protein levels in human liver cells. View Full-Text
Keywords: zearalenone; hepatotoxicity; oxidative stress; ER stress; phase I/II metabolism; apoptosis zearalenone; hepatotoxicity; oxidative stress; ER stress; phase I/II metabolism; apoptosis
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MDPI and ACS Style

Yoon, J.E.; Lee, K.Y.; Seok, J.S.; Cheng, W.N.; Kwon, H.C.; Jeong, C.H.; Han, S.G. Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells. Toxins 2020, 12, 2.

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