Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice

Abstract

Acetaminophen can induce liver injury with variable clinical outcome. We show that acetaminophen-induced hepatotoxicity is potentiated by activation of the transcription factor aryl hydrocarbon receptor (Ahr). Therefore, varying exposition to activating Ahr ligands might explain individual sensitivity to acetaminophen.BACKGROUND & AIMS: Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and metabolic signals into complex cellular transcriptional programs, might act as a rheostat for APAP-toxicity. METHODS: Wildtype or conditional Ahr knockout mice lacking Ahr in hepatocytes (Alb D/DAhr ) or myeloid cells (LysM D/DAhr ) were treated with the specific Ahr ligand 2-(1'H-indole-3'carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) together with APAP.RESULTS: Ahr activation by ITE, which by itself was non-toxic, exacerbated APAP-induced hepatotoxicity compared to vehicletreated controls, causing 80% vs. 0% mortality after administration of a normally sublethal APAP overdose. Of note, Ahr activation induced hepatocyte death even at APAP doses within the therapeutic range. Aggravated liver injury was associated with significant neutrophil infiltration; however, lack of Ahr in myeloid cells did not protect LysM D/DAhr mice from exacerbated APAP hepatotoxicity. In contrast, Alb D/DAhr mice were largely protected from ITE-induced aggravated liver damage, indicating that Ahr activation in hepatocytes, but not in myeloid cells, was instrumental for disease exacerbation. Mechanistically, Ahr activation fueled hepatic accumulation of toxic APAP metabolites by up-regulating expression of the APAPmetabolizing enzyme Cyp1a2, a direct Ahr downstream target.CONCLUSIONS: Ahr activation in hepatocytes potentiates APAP-induced hepatotoxicity. Thus, individual exposition to environmental Ahr ligands might explain individual sensitivity to hyperacute liver failure.

The aryl hydrocarbon receptor in liver inflammation

“…AHR controls protective IL-22 expression in ILCs and CD4+ T cells [34,35,37]. (C) APAPinduced liver injury: AHR activation induces the APAP-metabolizing enzyme CYP1A2, resulting in increased hepatotoxicity [52]. (D) Alcohol-induced liver injury: AHR activation reduces EtOH-induced oxidative stress, inflammation, and hepatocyte apoptosis [49,50].…”

“…Therefore, endogenous AHR ligands that can be produced by the intestinal microbiome might increase susceptibility to APAP hepatotoxicity. Note that presumably depending on the underlying pathogenic mechanisms, hepatic AHR activation can have both beneficial effects, as described in alcohol-induced liver injury [49,50], and detrimental effects, as shown for acetaminophen-induced acute liver injury [52].…”

“…Although here, the underlying molecular mechanisms were not focus of the study, it is likely that dysbiosis was accompanied with changes in gut bacteria-derived metabolites, including AHR ligands. Accordingly, in our recent study, we demonstrated that the tryptophan derivative ITE that can be produced in the gut strongly exacerbated acetaminophen (APAP)-induced hepatotoxicity by directly activating AHR and the APAPmetabolizing enzyme CYP1A2 in hepatocytes [52]. Therefore, endogenous AHR ligands that can be produced by the intestinal microbiome might increase susceptibility to APAP hepatotoxicity.…”

Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression

“…Induction of acute liver injury by acetaminophen (APAP) was conducted as previously described [16,17]. Briefly, the mice were fasted overnight prior to intraperitoneal administration of a single dose of APAP (300 mg/kg b.w.…”

Subcellular spatio-temporal intravital kinetics of aflatoxin B1 and ochratoxin A in liver and kidney

“…However, even relatively advanced PBPK models consider individual organs as single compartments (Thiel et al 2015 ) or at most differentiate a limited number of compartments within one organ (Bartl et al 2015 ; Ghallab et al 2016 ; Schliess et al 2014 ). Relatively little is known about local concentrations in sub-compartments of tissues (Reif et al 2017 ; Schneider et al 2021 ; Schuran et al 2021 ). Experimentally, local distributions of test compounds in tissues can be analyzed by autoradiography (Groothuis et al 1982 ).…”