Regulation of Drug Metabolism by the Interplay of Inflammatory Signaling, Steatosis, and Xeno-Sensing Receptors in HepaRG Cells.

Nonalcoholic fatty liver disease (NAFLD), which is characterized by triglyceride deposition in hepatocytes resulting from imbalanced lipid homeostasis, is of increasing concern in Western countries, along with progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Previous studies suggest a complex, mutual influence of hepatic fat accumulation, NASH-related inflammatory mediators, and drug-sensing receptors regulating xenobiotic metabolism. Here, we investigated the suitability of human HepaRG hepatocarcinoma cells as a model for NAFLD and NASH. Cells were incubated for up to 14 days with an oleate/palmitate mixture (125 µM each) and/or with 10 ng/ml of the inflammatory mediator interleukin-6 (IL-6). Effects of these conditions on the regulation of drug metabolism were studied using xenobiotic agonists of the aryl hydrocarbon receptor (AHR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), nuclear factor (erythroid-derived 2)-like 2, and peroxisome proliferator-activated receptor α (PPARα). Results underpin the suitability of HepaRG cells for NAFLD- and NASH-related research and constitute a broad-based analysis of the impact of hepatic fatty acid accumulation and inflammation on drug metabolism and its inducibility by xenobiotics. IL-6 exerted pronounced negative regulatory effects on basal as well as on PXR-, CAR-, and PPARα-, but not AHR-dependent induction of drug-metabolizing enzymes. This inhibition was related to diminished transactivation potential of the respective receptors rather than to reduced transcription of nuclear receptor-encoding mRNAs. The most striking effects of IL-6 and/or fatty acid treatment were observed in HepaRG cells after 14 days of treatment, making these cultures appear a suitable model for studying the relationship of fatty acid accumulation, inflammation, and xenobiotic-induced drug metabolism.

Cornflower Honey as a Model for Authentication of Unifloral Honey Using Classical Methods Combined with Plant-Based Marker Substances Such as Lumichrome.

According to legislation, unifloral honeys are characterized by their organoleptic, physicochemical, and microscopic properties. Melissopalynology is the established method for identifying the pollen taken up with the floral nectar by forager bees and is used for authentication of the nectar sources in honey. For cornflower honey (Centaurea cyanus), the pollen input does not correlate with the nectar input, because the nectar is produced both in floral and in extrafloral nectaries. The well-known cornflower marker lumichrome has now also been detected in the extrafloral nectar. Therefore, lumichrome is a suitable marker substance for cornflower honey. Four different methods for the sole analysis of lumichrome in honey were validated and compared. Studies over nine years have shown that unifloral cornflower honey should contain approximately 35 mg/kg lumichrome. For a further differentiated cornflower honey specific verification, other nonvolatile compounds like 7-carboxylumichrome and volatiles, such as 3,4-dihydro-3-oxoedulan I and 3,4-dihydro-3-oxoedulan II, should be analyzed. This enables a more specific accuracy for the classification of unifloral cornflower honey.