Khellin and Visnagin Differentially Modulate AHR Signaling and Downstream CYP1A Activity in Human Liver Cells

Abstract

Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1), which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE)-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co-administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones.

The Janus-Faced Role of Aryl Hydrocarbon Receptor Signaling in the Skin: Consequences for Prevention and Treatment of Skin Disorders

“…Accordingly, activation of AHR in healthy skin by PAH and UV-B radiation induces cellular events, which may foster the generation of reactive metabolites and the accumulation of damaged macromolecules and thereby initiate extrinsic aging processes and carcinogenesis (Esser et al, 2013;Esser and Rannug, 2015). AHR is a negative regulator of apopotosis in UV-B-damaged keratinocytes, indicating its involvement in initiation of skin cancer (Frauenstein et al, 2013). In addition, enhanced production of cytochrome P450 1 enzymes may lead to the generation of reactive oxygen species (ROS) and mutagenic PAH metabolites, which may damage proteins and DNA (Ioannides and Lewis, 2004).…”

Environmental pollutants parathion, paraquat and bisphenol A show distinct effects towards nuclear receptors-mediated induction of xenobiotics-metabolizing cytochromes P450 in human hepatocytes

“…Extraction of total proteins and SDS-PAGE were performed as described elsewhere (Vrzal et al, 2013). Blots were probed with primary antibodies against CYP1A1 (goat polyclonal; sc-9828, G-18), CYP1A2 (mouse monoclonal; sc-53614, 3B8C1), CYP3A4 (mouse monoclonal; sc-53850, HL3), CYP2A6 (mouse monoclonal; sc-53615, F16 P2 D8), CYP2B6 (rabbit polyclonal; sc-67224, H-110), AhR (mouse monoclonal; sc-133088, A-3), PXR (mouse monoclonal; sc-48340, H-11) and actin (goat polyclonal; sc-1616, 1-19), all purchased from Santa Cruz Biotechnology (Santa Cruz, CA).…”

“…pesticides, flame retardants, plasticizers or dyes may have adverse effects on human health, as revealed by numerous epidemiological studies (Gascon et al, 2014(Gascon et al, , 2015Valvi et al, 2014;Shim et al, 2009;Dahlgren et al, 2003). There is a great number of data in the literature describing induction of xenobiotics-metabolizing human cytochromes P450 by food contaminants and environmental pollutants (Novotna and Dvorak, 2014;Vrzal et al, 2013;Kamenickova et al, 2013;Ayed-Boussema et al, 2012;Lee et al, 2006;Nekvindova et al, 2006). Interestingly, the effects of notoriously known and common environmental and food contaminants including parathion (PTH), bisphenol A (BPA) and paraquat (PRQ) (Fig.…”

The effects of drugs with immunosuppressive or immunomodulatory activities on xenobiotics-metabolizing enzymes expression in primary human hepatocytes

“…Total protein extracts and SDS-PAGE were performed as described elsewhere (Vrzal et al, 2013). Blots were probed with primary antibodies against CYP1A1 (goat polyclonal; sc-9828, G-18), CYP1A2 (mouse monoclonal; sc-53614, 3B8C1), CYP3A4 (mouse monoclonal; sc-53850, HL3), CYP2A6 (mouse monoclonal; sc-53615, F16 P2 D8), CYP2B6 (rabbit polyclonal; sc-67224, H-110), CYP2C9/19 (goat polyclonal; sc-23436, C-21) and actin (goat polyclonal; sc-1616, 1-19), all purchased from Santa Cruz Biotechnology (Santa Cruz, CA).…”