Abstract
Acetaminophen (APAP) overdose is very common worldwide and has been widely recognized as the leading cause of drug-induced liver injury in the Western world. In our previous investigation, auriculatone, a natural product firstly obtained from Aster auriculatus, has demonstrated a potent protective effect against APAP-induced hepatotoxicity in HL-7702 cells. However, the poor water solubility and low bioavailability restrict its application. Auriculatone sulfate (AS) is a sulfated derivative of auriculatone with highly improved water-solubility. Hepatoprotective effects against APAP-induced liver injury (AILI) showed that intragastric pretreatment with AS at 50 mg/kg almost completely prevented mice against APAP-induced increases of serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and ATPase. Histological results showed that AS could protect the liver tissue damage. In addition, AS pretreatment not only significantly retained hepatic malondialdehyde and the activities of glutathione, superoxide dismutase, and glutathione peroxidase at normal levels, but also markedly suppressed the increase of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels in mouse liver caused by overdose APAP. Immunohistochemical analysis showed that AS obviously attenuated the expression of CD45 and HNE in liver tissue. Further mechanisms of action investigation showed that inhibition of cytochrome P450 3A11 (CYP 3A11) and CYP2E1 enzymatic activities (but not that of CYP1A2) was responsible for APAP bioactivation. In conclusion, AS showed a hepatoprotective effect against AILI through alleviating oxidative stress and inflammation and inhibiting CYP-mediated APAP bioactivation. It may be an effective hepatoprotective agent for AILI and other forms of human liver disease.
Highlights
Drug-induced liver injury (DILI) has been the most common cause of acute liver failure in recent years [1]
APAP is metabolized mainly to sulfated and glucuronidated conjugates to be further excreted in the urine [3], while a minor portion of APAP is metabolized by cytochrome P450 enzymes (CYPs) (e.g., CYP1A2, CYP2E1, and CYP3A4) into an electrophilic and toxic form, N-acetyl-p-benzoquinone-imine (NAPQI) [4]
The results showed that an overdose of 300 mg/kg APAP could induce severe liver injury
Summary
Drug-induced liver injury (DILI) has been the most common cause of acute liver failure in recent years [1]. APAP overdose-induced liver injury is not uncommon worldwide and has been recognized as the leading cause of DILI in Great Britain and in the United States [2]. APAP is metabolized mainly to sulfated and glucuronidated conjugates to be further excreted in the urine [3], while a minor portion of APAP is metabolized by cytochrome P450 enzymes (CYPs) (e.g., CYP1A2, CYP2E1, and CYP3A4) into an electrophilic and toxic form, N-acetyl-p-benzoquinone-imine (NAPQI) [4]. An overdose of APAP can saturate its glucuronidation and sulfation, resulting in accumulation of NAPQI, excessive conjugation of which to GSH afterwards leads to depletion of the hepatic GSH pool.
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