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, 29 (3), 165-72

Recent Updates on Acetaminophen Hepatotoxicity: The Role of nrf2 in Hepatoprotection


Recent Updates on Acetaminophen Hepatotoxicity: The Role of nrf2 in Hepatoprotection

Sang Il Gum et al. Toxicol Res.


Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection.

Keywords: Acetaminophen; Hepatotoxicity; Natural product; Nrf2.


Fig. 1.
Fig. 1.. The metabolic pathways of APAP accompanied with efflux into the bile and urine in hepatocyte. More than 80~90% of APAP is conjugated with glucuronic acid or sulfate following renal excretion. A small fraction is metabolized by CYP to form the reactive metabolite NAPQI, which can be conjugated with GSH. The excretion of GSH conjugated metabolite into the bile and urine is depicted. The transport of the metabolite into the bile can initiate enterohepatic recirculation, which affects the development of hepatotoxicity. Unconjugated NAPQI covalently binds to a cellular protein under GSH depletion, which causes hepatocyte damage. acetaminophen, APAP; breast cancer resistance protein, Bcrp; cytochrome P450 2E1, CYP2E1; glutathione, GSH; glutathione S-transferase, GST; multidrug resistance-associated protein transporters, MRP; N-acetyl-p-benzoquinone imine, NAPQI; NF-E2 related factor2, Nrf2.
Fig. 2.
Fig. 2.. The Nrf2-dependent gene regulation. The Nrf2 released from Keap1 translocates to the nucleus through multiple upstream cell signaling pathways. Once in the nucleus, Nrf2 causes heterodimerization with a small Maf protein. This complex interacts with ARE in the promoter of target genes and activates gene transcription. The Nrf2-mediated gene battery in hepatocytes is shown. Some genes are negatively regulated by Nrf2. aldo-keto reductase 7A, Akr7a; glutamate cysteine ligase, GCL; glutathione S-transferase alpha2, GSTA2; heme oxygenase-1, HO-1; NAD(P)H:quinone oxidoreductase 1, NQO1; multidrug resistance-associated protein transporters, Mrp; orgarnic anion-transporting polypeptides, Oatp1al; protein tyrosine phosphatase 1B, PTP1B; thioredoxin reductase 1, Txnrd1.
Fig. 3.
Fig. 3.. The potential candidates from natural products against APAP hepatotoxicity. The Pie chart shows the percentage distribution of the target, the scientific name of plants and action targets studied. The natural products presented on the dotted line indicate the effect on both sides. A red dotted line in the chart displays the target of Panax ginseng C.A.Meyer. The original source of images for each plant is from the google site.

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