Abstract
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.
Highlights
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is relatively safe and effective at therapeutic doses
The present study demonstrated the protective effect of p53 on APAP-induced liver toxicity by regulating the expression of drug-metabolizing enzymes and transporters, which enhanced APAP metabolism and suppressed oxidative damage. p53-null mice were more susceptible to APAP-induced liver injury
An increase of UGTs, SULTs, and multidrug resistance-associated protein (MRP) expression was observed after p53 activation, indicating that Dox promotes the conversion of APAP to nontoxic metabolites as well as the elimination of APAP metabolites
Summary
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is relatively safe and effective at therapeutic doses. APAP in high doses leads to hepatotoxicity, which is recognized as a major cause of acute liver failure[1]. APAP is primarily catalyzed by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) to non-toxic metabolites[2]. NAPQI is normally detoxified by conjugation to glutathione (GSH), which is further excreted in urine by multidrug resistance-associated protein (MRP). The massive accumulation of NAPQI depletes GSH, which induces oxidative stress and lead to hepatocellular damage[4]. Glutathione S-transferases (GSTs) and NAD(P)H Quinone Dehydrogenase 1 (NQO1) are involved in the detoxification of APAP by regulating GSH homeostasis[5]. N-acetylcysteine has been clinically used as Official journal of the Cell Death Differentiation Association
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
