title: The amelioration of N-acetyl-p-benzoquinone imine toxicity by ginsenoside Rg3: the role of Nrf2-mediated detoxification and Mrp1/Mrp3 transports.
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 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. Rg3 pretreatment reversed GSH depletion by NAPQI. 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. 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 Rg3. Abolishment of the reversal of GSH depletion by Rg3 against NAPQI was observed in Nrf2-deficient cells. Rg3 induced multidrug resistance-associated protein (Mrp) 1 and Mrp3 mRNA levels, but not in Nrf2-deficient cells. Taken together, these results demonstrate that 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.
authors.affiliation: Department of Pharmacology, College of Oriental Medicine, Dongguk University, Kyungju, Republic of Korea.
authors.forename: Sang Il
authors.initials: SI
authors.lastname: Gum
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Cho
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D036145:Ginsenosides / Q000737:chemistry / Q000494:pharmacology*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D007097:Imines / Q000633:toxicity*; D008658:Inactivation, Metabolic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats
chemical_list: D016227:Benzoquinones; D036145:Ginsenosides; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D007097:Imines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; C114462:multidrug resistance-associated protein 3; C097367:ginsenoside Rg3; C028473:N-acetyl-4-benzoquinoneimine; C421109:multidrug resistance-associated protein 1