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.
Highlights
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses
Much APAP is metabolized via conjugation with glucuronic acid and sulfate and excreted, a portion of APAP is converted by cytochrome P-450 metabolism to a reactive quinone form, N-acetyl-p-benzoquinone imine (NAPQI), which is inactivated by conjugation with glutathione (GSH) [4]
The protective effects of adenosine 5′-monophosphate (5′-AMP) (15, 20 mg/g) was detectable macroscopically on liver appearance, with strong hepatic injury changes in livers derived from APAP-treated mice, but normal liver morphology in the mice treated with co-administration of APAP and 5′-AMP (Figure 1B)
Summary
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses. When take at high doses or, rarely in susceptible people at therapeutic doses, APAP can precipitate severe liver injury that can develop into acute liver failure [1,2]. APAP overdose is the most frequent cause of drug-induced liver failure in the some developed countries [3]. Much APAP is metabolized via conjugation with glucuronic acid and sulfate and excreted, a portion of APAP is converted by cytochrome P-450 metabolism to a reactive quinone form, N-acetyl-p-benzoquinone imine (NAPQI), which is inactivated by conjugation with glutathione (GSH) [4]. Once the pool of GSH is exhausted, any remained N-acetyl-p-benzoquinone imine covalently binds cellular macromolecules induces a series of molecular events that include alkylation of proteins, membrane lipid peroxidation, mitochondrial dysfunction, imbalance of intracellular calcium, formation of reactive oxygen species and reactive nitrogen species [5,6]. APAP-induced hepatocellular damage and necrotic and apoptotic cell death can result in severe centrilobular hepatotoxicity and acute liver failure [7,8]
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