Abstract
The interactions between pharmaceuticals and nanomaterials and its potentially resulting toxicological effects in living systems are only insufficiently investigated. In this study, two model compounds, acetaminophen, a pharmaceutical, and cerium dioxide, a manufactured nanomaterial, were investigated in combination and individually. Upon inhalation, cerium dioxide nanomaterials were shown to systemically translocate into other organs, such as the liver. Therefore we picked the human liver cell line HuH-7 cells as an in vitro system to investigate liver toxicity. Possible synergistic or antagonistic metabolic changes after co-exposure scenarios were investigated. Toxicological data of the water soluble tetrazolium (WST-1) assay for cell proliferation and genotoxicity assessment using the Comet assay were combined with an untargeted as well as a targeted lipidomics approach. We found an attenuated cytotoxicity and an altered metabolic profile in co-exposure experiments with cerium dioxide, indicating an interaction of both compounds at these endpoints. Single exposure against cerium dioxide showed a genotoxic effect in the Comet assay. Conversely, acetaminophen exhibited no genotoxic effect. Comet assay data do not indicate an enhancement of genotoxicity after co-exposure. The results obtained in this study highlight the advantage of investigating co-exposure scenarios, especially for bioactive substances.
Highlights
Drug-induced liver injury (DILI) is a common cause for acute liver failure, affecting patients, and drug developers, drug regulating authorities and health care providers [1,2]
The NPs used in this study (NM212, Joint Research Centre (JRC)) were comprehensively investigated by the manufacturer as well as in the frame of several research projects [13,15]
The results show significant differences between HuH-7 cell membrane lipid lipid patterns for cells exposed to 5 mmol
Summary
Drug-induced liver injury (DILI) is a common cause for acute liver failure, affecting patients, and drug developers, drug regulating authorities and health care providers [1,2]. APAP overdose causes severe liver toxicity and may even result in death [4]. The toxicity of APAP is caused via the generation of the reactive N-acetyl-p-benzoquinone imine (NAPQI) during phase I of hepatic biotransformation, followed by cell necrosis and/or apoptosis of the hepatocytes exposed [1]. NPs are known to cause toxicity via the generation of reactive oxygen species (ROS) [5] and may, affect the pathogenesis of DILI. CeO2 based nanocarriers were already successfully employed as a inflammatory regulator by utilizing their scavenging activity of ROS in DILI [7].
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