Okadaic Acid Activates JAK/STAT Signaling to Affect Xenobiotic Metabolism in HepaRG Cells

Abstract

Okadaic acid (OA) is a marine biotoxin that is produced by algae and accumulates in filter-feeding shellfish, through which it enters the human food chain, leading to diarrheic shellfish poisoning (DSP) after ingestion. Furthermore, additional effects of OA have been observed, such as cytotoxicity. Additionally, a strong downregulation of the expression of xenobiotic-metabolizing enzymes in the liver can be observed. The underlying mechanisms of this, however, remain to be examined. In this study, we investigated a possible underlying mechanism of the downregulation of cytochrome P450 (CYP) enzymes and the nuclear receptors pregnane X receptor (PXR) and retinoid-X-receptor alpha (RXRα) by OA through NF-κB and subsequent JAK/STAT activation in human HepaRG hepatocarcinoma cells. Our data suggest an activation of NF-κB signaling and subsequent expression and release of interleukins, which then activate JAK-dependent signaling and thus STAT3. Moreover, using the NF-κB inhibitors JSH-23 and Methysticin and the JAK inhibitors Decernotinib and Tofacitinib, we were also able to demonstrate a connection between OA-induced NF-κB and JAK signaling and the downregulation of CYP enzymes. Overall, we provide clear evidence that the effect of OA on the expression of CYP enzymes in HepaRG cells is regulated through NF-κB and subsequent JAK signaling.

Paclitaxel- and vincristine-induced neurotoxicity and drug transport in sensory neurons

“…Surrogate peptides and internal standard peptides were precipitated using triple X proteomics (TXP) antibodies. Peptides were then eluted and quantified using a modified version of the previously described LC–MS methods (28,29): There, 6 min and 10 min parallel reaction monitoring (PRM) methods are described (UltiMate 3000 RSLCnano and PRM–QExactive Plus; Thermo Scientific, Waltham, MA, USA). Raw data were processed using TraceFinder 4.1 (Thermo Scientific, Waltham, MA, USA).…”

Unnatural Endotype B PPAPs as Novel Compounds with Activity against Mycobacterium tuberculosis

“…Surrogate peptides and internal standard peptides were precipitated by using triple X proteomics (TXP) antibodies. Peptides were then eluted and quantified using a modified version of the previously described LC–MS methods , : There, 6 min parallel reaction monitoring (PRM) methods were described (UltiMate 3000 RSLCnano and PRM–QExactive Plus; Thermo Fisher Scientific, Waltham, MA, USA). Raw data were processed using TraceFinder 4.1 (Thermo Fisher Scientific, Waltham, MA, USA).…”

Effects of marine biotoxins on drug-metabolizing cytochrome P450 enzymes and their regulation in mammalian cells

“…Accordingly, the AHR, activated for example by dioxins and polycyclic aromatic hydrocarbons, is a major transcriptional regulator of the expression of CYP family 1 members (Abel and Haarmann-Stemmann 2010 ; Haarmann-Stemmann and Abel 2006 ). CYP 1 regulation by marine biotoxins was investigated in 10 different papers (Alarcan et al 2017 ; Ferron et al 2016 ; Hukkanen et al 2000 ; Oesch-Bartlomowicz et al 1997 ; Posti et al 1999 ; Shimoyama et al 2014 ; Sidhu and Omiecinski 1997 ; Tamaki et al 2005 ; Wuerger et al 2022 ; Wuerger et al 2023 ), with a total of 21 different entries for individual CYPs, experimental systems and toxins. A summary of the observations along with the respective references is provided in Table 1 .…”

“…Effects of marine biotoxins on CYP family 1 members might, in principle, be indirectly caused by interference with the xeno-sensor and key CYP1A/CYP1B regulator AHR. No or only minor effects of OA on AHR expression or activity were observed in some studies with different models (Alarcan et al 2017 ; Kurl 1994 ; Shimoyama et al 2014 ); or downregulation of AHR expression in human cells occurred only at OA concentrations much higher than needed for CYP1A1/1A2 repression (Wuerger et al 2022 ). This may indicate that a mechanism distinct from simple regulation of the overall cellular amount of the AHR is responsible for the OA-mediated decrease in CYP1A.…”

“…Besides documented effects on the physical intestinal barrier, it has recently been demonstrated that OA affects the expression of various CYP isoform relevant for drug and xenobiotic metabolism in human HepaRG liver cells in vitro (Wuerger et al 2022 , 2023 ), suggesting that also in vivo the biochemical barrier function of the organ is likely to be affected. This aspect of toxicity has not yet been much in the focus of research on marine biotoxins.…”