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Comparative Analysis and Functional Characterization of HC-AFW1 Hepatocarcinoma Cells: CYP Expression and Induction by Nuclear Receptor Agonists

Abstract:

Enzymatic conversion of most xenobiotic compounds is accomplished by hepatocytes in the liver, which are also an important target for the manifestation of the toxic effects of foreign compounds. Most cell lines derived from hepatocytes lack important toxifying or detoxifying enzymes or are defective in signaling pathways which regulate expression and activity of these enzymes. On the other hand, the use of primary human hepatocytes is complicated by scarce availability of cells and high inter-donor variability. Thus, analyses of drug metabolism and hepatotoxicity in vitro are a difficult task. The cell line HC-AFW1 was isolated from a pediatric hepatocellular carcinoma and so far has been used for tumorigenicity and chemotherapy resistance studies. Here, a comprehensive characterization of xenobiotic metabolism in HC-AFW1 cells is presented along with studies on the functionality of the most important transcriptional regulators of drug-metabolizing enzymes. Results from HC-AFW1 cells were compared to commercially available HepaRG cells and to cultured primary human hepatocytes. Data show that the nuclear receptors and xenosensors AHR (aryl hydrocarbon receptor), CAR (constitutive androstane receptor), PXR (pregnane-X-receptor), NRF2 (nuclear factor (erythroid-derived 2)-like 2), and PPARalpha (peroxisome proliferator-activated receptor alpha) are functional in HC-AFW1 cells, comparable to HepaRG and primary cells. HC-AFW1 cells possess considerable activities of different cytochrome P450 (CYP) enzymes, which, however, are lower than corresponding enzyme activities in HepaRG cells or primary hepatocytes. In summary, HC-AFW1 are a new promising tool for studying the mechanisms of the regulation of drug metabolism in human liver cells in vitro.

26310804

Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes

Drug Metab Dispos
Drug Metab Dispos. 2015 Aug 26. pii: dmd.115.064667.
28th Aug 2015

A. Braeuning, M. Thomas, U. Hofmann, S. Vetter, E. Zeller, B. Petzuch, J. Johanning, W. Schroth, T. S. Weiss, U. M. Zanger, M. Schwarz

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[Maria Thomas] [Ute Hofmann] [Thomas Weiss] [Ulrich Zanger]

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Views: 1137
  • Created: 17th Sep 2015 at 10:17

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