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Ochratoxin A-Induced Hepatotoxicity through Phase I and Phase II Reactions Regulated by AhR in Liver Cells

1
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
2
School of Food Science, University of Idaho, 875 Perimeter Drive, Moscow, MS 2312, USA
*
Author to whom correspondence should be addressed.
Toxins 2019, 11(7), 377; https://doi.org/10.3390/toxins11070377
Received: 3 June 2019 / Revised: 17 June 2019 / Accepted: 25 June 2019 / Published: 29 June 2019
(This article belongs to the Special Issue Ochratoxin in Food Safety and Public Health)
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Abstract

Ochratoxin A (OTA) is a widespread mycotoxin produced by several species of the genera Aspergillus and Penicillium. OTA exists in a variety of foods, including rice, oats, and coffee and is hepatotoxic, with a similar mode of action as aflatoxin B1. The precise mechanism of cytotoxicity is not yet known, but oxidative damage is suspected to contribute to its cytotoxic effects. In this study, human hepatocyte HepG2 cells were treated with various concentrations of OTA (5–500 nM) for 48 h. OTA triggered oxidative stress as demonstrated by glutathione depletion and increased reactive oxygen species, malondialdehyde level, and nitric oxide production. Apoptosis was observed with 500 nM OTA treatment. OTA increased both the mRNA and protein expression of phase I and II enzymes. The same results were observed in an in vivo study using ICR mice. Furthermore, the relationship between phase I and II enzymes was demonstrated by the knockdown of the aryl hydrocarbon receptor (AhR) and NF-E2-related factor 2 (Nrf2) with siRNA. Taken together, our results show that OTA induces oxidative stress through the phase I reaction regulated by AhR and induces apoptosis, and that the phase II reaction is activated by Nrf2 in the presence of oxidative stress. View Full-Text
Keywords: hepatotoxicity; ochratoxin A; oxidative stress; phase I reaction; phase II reaction hepatotoxicity; ochratoxin A; oxidative stress; phase I reaction; phase II reaction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Shin, H.S.; Lee, H.J.; Pyo, M.C.; Ryu, D.; Lee, K.-W. Ochratoxin A-Induced Hepatotoxicity through Phase I and Phase II Reactions Regulated by AhR in Liver Cells. Toxins 2019, 11, 377.

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