Adenosine 5′-monophosphate blocks acetaminophen toxicity by increasing ubiquitination-mediated ASK1 degradation

Abstract

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the world. Hepatic c-jun NH2-terminal protein kinase (JNK) activation is thought to be a consequence of oxidative stress produced during APAP metabolism. Activation of JNK signals causes hepatocellular damage with necrotic and apoptotic cell death. Here we found that APAP caused a feedback increase in plasma adenosine 5′-monophsphate (5′-AMP). We demonstrated that co-administration of APAP and 5′-AMP significantly ameliorated APAP-induced hepatotoxicity in mice, without influences on APAP metabolism and its analgesic function. The mechanism of protection by 5′-AMP was through inhibiting APAP-induced activation of JNK, and attenuating downstream c-jun and c-fos gene expression. This was triggered by attenuating apoptosis signal-regulated kinase 1(ASK1) methylation and increasing ubiquitination-mediated ASK1 protein degradation. Our findings indicate that replacing the current APAP with a safe and functional APAP/5′-AMP formulation could prevent APAP-induced hepatotoxicity.

JNK Signaling Pathway Mediates Acetaminophen-Induced Hepatotoxicity Accompanied by Changes of Glutathione S-Transferase A1 Content and Expression

“…In addition, we measured the activation of c-Fos, reported as downstream of JNK signaling pathway (Yang et al, 2016b). Acetaminophen caused a marked increase on c-Fos activation, but SP600125 did not inhibit the activation.…”

Crystallographic mining of ASK1 regulators to unravel the intricate PPI interfaces for the discovery of small molecule

“…However, PRMT5 does the methylation of R89 in ASK1 and promotes the interaction between ASK1 and Akt, thus advancing S83 phosphorylation and ASK1 negative regulation [226] . Moreover, in a study, it has been reported that 5′-AMP administration weakens ASK1 methylation and enhances ubiquitination, which therefore prompts ASK1 degradation, inferring that ASK1 methylation could add to its stability [227] .…”