Abstract
Acetaminophen (APAP), which is also known as paracetamol or N-acetyl-p-aminophenol is a safe and potent drug for fever, pain and inflammation when used at its normal therapeutic doses. It is available as over-the-counter drug and used by all the age groups. The overdose results in acute liver failure that often requires liver transplantation. Current clinical therapy for APAP-induced liver toxicity is the administration of N-acetyl-cysteine (NAC), a sulphydryl compound an approved drug which acts by replenishing cellular glutathione (GSH) stores in the liver. Over the past five decades, several studies indicate that the safety and efficacy of herbal extracts or plant derived compounds that are used either as monotherapy or as an adjunct therapy along with conventional medicines for hepatotoxicity have shown favorable responses. Phytochemicals mitigate necrotic cell death and protect against APAP-induced liver toxicityby restoring cellular antioxidant defense system, limiting oxidative stress and subsequently protecting mitochondrial dysfunction and inflammation. Recent experimental evidences indicat that these phytochemicals also regulate differential gene expression to modulate various cellular pathways that are implicated in cellular protection. Therefore, in this review, we highlight the role of the phytochemicals, which are shown to be efficacious in clinically relevant APAP-induced hepatotoxicity experimental models. In this review, we have made comprehensive attempt to delineate the molecular mechanism and the cellular targets that are modulated by the phytochemicals to mediate the cytoprotective effect against APAP-induced hepatotoxicity. In this review, we have also defined the challenges and scope of phytochemicals to be developed as drugs to target APAP-induced hepatotoxicity.
Highlights
Acetaminophen (APAP), which is known as paracetamol or N-acetyl-p-aminophenol appears as a safe and potent drug for fever, pain and inflammation at its normal therapeutic doses
APAP is metabolized by sulfation and glucuronidation in liver with less than 5–10% being metabolized by the hepatic cytochrome P450 (CYP450) system
The phytochemicals that are enumerated in this review have shown to attenuate liver injury either in the in vitro; cell-based assays or in vivo; in rats and mice models of liver toxicity in preclinical studies
Summary
Acetaminophen (APAP), which is known as paracetamol or N-acetyl-p-aminophenol appears as a safe and potent drug for fever, pain and inflammation at its normal therapeutic doses. Since the recognition of APAP associated liver toxicity in 1960s, experimental models including both in vivo (animal models) and in vitro (cell lines) have been employed for screening hepatoprotective properties [22,23] either of synthetic origin or plant derived natural extracts. Most of the plant extracts have been reported hepatoprotective based on the biochemical and histopathological assessments of liver injury and protection These natural drugs appear hepatoprotective by restoring the antioxidant defense, preventing the occurrence of oxidative stress and subsequently curbing mitochondrial dysfunction and inflammation, as well as limiting the resultant necrotic cell death [25,26]. Each phytochemical has been discussed emphasizing their source, chemical name and their effect as well as underlying mechanism in countering APAP-induced liver toxicity
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