The Food Contaminants Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis Structure-Dependently in the Human Hepatoma Cell Line HepaRG.

Josephin Glück,Marcus Henricsson,Stefanie Hessel-Pras,Albert Braeuning

doi:10.3390/foods10051114

Abstract

Pyrrolizidine alkaloids (PAs) are a group of secondary plant metabolites being contained in various plant species. The consumption of contaminated food can lead to acute intoxications in humans and exert severe hepatotoxicity. The development of jaundice and elevated bile acid concentrations in blood have been reported in acute human PA intoxication, indicating a connection between PA exposure and the induction of cholestasis. Additionally, it is considered that differences in toxicity of individual PAs is based on their individual chemical structures. Therefore, we aimed to elucidate the structure-dependent disturbance of bile acid homeostasis by PAs in the human hepatoma cell line HepaRG. A set of 14 different PAs, including representatives of all major structural characteristics, namely, the four different necine bases retronecine, heliotridine, otonecine and platynecine and different grades of esterification, was analyzed in regard to the expression of genes involved in bile acid synthesis, metabolism and transport. Additionally, intra- and extracellular bile acid levels were analyzed after PA treatment. In summary, our data show significant structure-dependent effects of PAs on bile acid homeostasis. Especially PAs of diester type caused the strongest dysregulation of expression of genes associated with cholestasis and led to a strong decrease of intra- and extracellular bile acid concentrations.

Highlights

Competent HepaRG cells were treated with the 22 pyrrolizidine alkaloids (PAs) for 24 h at six different concentrations ranging from 0.1 to 250 μM
We have shown that PAs have a significant structure-dependent effect on bile acid homeostasis
We were able to demonstrate that especially PAs of the diester type caused strongest dysregulation of expression of several genes responsible for bile acid synthesis, uptake and secretion in HepaRG cells

Summary

Introduction

Secondary plant compounds have increasingly come into the focus of risk assessment as food contaminants in recent years. One group of these contaminants are the. Humans are exposed to PAs mainly via the consumption of contaminated food. The Federal Institute for Risk Assessment identified in 2013 tea, herbal teas and honey as the main sources for human PA uptake in Western countries [1]. A consumption of contaminated salad mixes, herbs, flour or cereals can lead to the uptake of substantial amounts of PA [2,3,4,5]. There are some plants used as food that produce PA themselves such as borage. Chen et al [6]

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