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The amelioration of N-acetyl-p-benzoquinone imine toxicity by ginsenoside Rg3: the role of Nrf2-mediated detoxification and Mrp1/Mrp3 transports

Significance Statement

The protective effects of Korean red ginseng and ginsenoside Rg3  against overdose APAP in hepatocyte.

APAP is predominantly conjugated into glucuronide and sulfate moieties (detoxification pathway). When the conjugation enzymes are saturated, excess APAP is increasingly metabolized into a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome P450 2E1 (CYP2E1) (Phase I metabolism). The NAPQI is subsequently conjugated with glutathione (GSH), which is facilitated by GSTA2 (Phase II metabolism). Unconjugated NAPQI covalently binds to cellular proteins under GSH depletion, which causes hepatocellular necrosis (toxification pathway). GSH-conjugated metabolite is transported into the bile and blood (Phase III metabolism). The transport of the metabolite into the bile can initiate enterohepatic recirculation, which affects the development of hepatotoxicity (toxification pathway). The protective effects of Korean red ginseng and ginsenoside Rg3  against APAP-induced hepatotoxicity are caused by modulation in the APAP metabolism (Phase I, phase II and phase III). NF-E2 related factor2 plays a critical role in the regulation of genes related to APAP metabolism and is considered to be the most important target of Korean red ginseng and Rg3.

Acetaminophen, APAP; cytochrome P450 2E1, CYP2E1; glutamate cysteine ligase catalytic subunit, GCLC; glutamate cysteine ligase modulatory subunit, GCLM; glutathione, GSH; glutathione S-transferase, GST; multidrug resistance protein, MDR; multidrug resistance-associated protein transporters, MRP; N-acetyl-p-benzoquinone imine, NAPQI.

 

The amelioration of N-acetyl-p-benzoquinone imine toxicity by ginsenoside Rg3: the role of Nrf2-mediated detoxification and Mrp1/Mrp3 transports- Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Gum SI, Cho MK.

Oxid Med Cell Longev. 2013;2013:957947.

Department of Pharmacology, College of Oriental Medicine, Dongguk University, Kyungju, Republic of Korea.

Abstract

Previously, we found that Korean red ginseng suppressed acetaminophen (APAP)-induced hepatotoxicity via alteration of its metabolic profile involving GSTA2 induction and that ginsenoside Rg3 was a major component of this gene induction. In the present study, therefore, we assessed the protective effect of ginsenoside Rg3  against N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolic intermediate of APAP. Excess NAPQI resulted in GSH depletion with increases in the ALT and AST activities in H4IIE cells. Ginsenoside Rg3  pretreatment reversed GSH depletion by NAPQI. Ginsenoside Rg3  resulted in increased mRNA levels of the catalytic and modulatory subunit of glutamate cysteine ligase (GCL), the rate-limiting steps in GSH synthesis and subsequently increased GSH content. Ginsenoside Rg3  increased levels of nuclear Nrf2, an essential transcriptional factor of these genes. The knockdown or knockout of the Nrf2 gene abrogated the inductions of mRNA and protein by ginsenoside Rg3 . Abolishment of the reversal of GSH depletion by ginsenoside Rg3  against NAPQI was observed in Nrf2-deficient cells. Ginsenoside Rg3  induced multidrug resistance-associated protein (Mrp) 1 and Mrp3 mRNA levels, but not in Nrf2-deficient cells. Taken together, these results demonstrate that ginsenoside Rg3  is efficacious in protecting hepatocytes against NAPQI insult, due to GSH repletion and coordinated gene regulations of GSH synthesis and Mrp family genes by Nrf2.

 

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