Activation of the arylhydrocarbon receptor sensitizes to acetaminophen-induced acute liver failure

Question:

Acetaminophen (APAP)- induced liver damage is one of the most common causes of acute liver failure. However, the risk factors determining hypersensitivity to APAP remain poorly defined. The transcription factor arylhydrocarbon receptor (AhR), which can be activated by environmental, dietary, microbial and metabolic ligands, is a direct inducer of CYP1A2, one of the major enzymes involved in the generation of toxic APAP metabolites. Therefore, we hypothesized that AhR activation might contribute to APAP-induced hepatotoxicity.

Methods:

Wildtype or conditional AhR knockout mice lacking AhR in hepatocytes (AlbΔ/ΔAhR) were subjected to a combined treatment with APAP and the non-toxic gut-derived AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE).

Results:

Administration of ITE together with a normally sublethal APAP overdose (350 mg/kg) caused 80% mortality within 8 hours, whereas all vehicle-treated control mice survived (p = 0.0002). Accordingly, we found vast necrotic areas in liver tissue (p < 0.0001) and strongly elevated serum transaminase levels (ALT: 7616 vs. 812 U/L, p < 0.0001) in mice, which were co-treated with ITE and APAP, as compared to controls receiving vehicle and APAP. Of note, even at APAP doses equivalent to the recommended therapeutic range in humans, AhR activation by ITE induced substantial liver damage as compared to vehicle treatment (ALT: 1488 vs. 117 U/L, p = 0.0043). In contrast, AlbΔ/ΔAhR mice were largely protected from ITE-induced disease aggravation. Indeed, serum ALT levels (1063 vs. 3247 U/L), p = 0.0012) were significantly lower as compared to littermate controls. Moreover, TUNEL staining of liver sections revealed greatly reduced hepatocyte death in AlbΔ/ΔAhR mice following combined APAP and ITE treatment (p = 0.007). Mechanistically, AhR activation by ITE fueled hepatic accumulation of toxic APAP metabolites by up-regulating expression of the APAP-metabolizing enzymes CYP1A2 (p < 0.0001) and CYP2E1 (p = 0.0077), and of the glutathione-degrading enzyme gamma-glutamyltransferase (GGT) (p = 0.0001).

Conclusion:

AhR activation in hepatocytes induces accumulation of toxic APAP metabolites aggravating APAP hepatotoxicity. Thus, AhR activating ligands, which can originate from various sources, such as nutrition or gut microbiota, might be a risk factor sensitizing to APAP-induced acute liver failure.