Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways.
Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury.
Department of Pharmacology, Dalian Medical University, Dalian 116044, China; Department of Pharmacy, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
Musen
M
Lin
Department of Pharmacology, Dalian Medical University, Dalian 116044, China; Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
Xiaohan
X
Zhai
Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
Guangzhi
G
Wang
Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
Xiaofeng
X
Tian
Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
Dongyan
D
Gao
Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
Lei
L
Shi
Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
Hang
H
Wu
Department of Pharmacy, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
Qing
Q
Fan
Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
Jinyong
J
Peng
Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
Kexin
K
Liu
Department of Pharmacology, Dalian Medical University, Dalian 116044, China; Research Institute of Integrated Traditional and Western Medicine of Dalian Medical University, Dalian 116044, China. Electronic address: yaojihong65@hotmail.com.
Jihong
J
Yao
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001572:Benzofurans / Q000302:isolation & purification / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D050217:Metabolic Detoxication, Phase II / Q000235:genetics*; D008815:Mice, Inbred Strains; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D027561:Salvia miltiorrhiza / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D053630:Depsides
D000082:Acetaminophen; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001572:Benzofurans; D005721:Glutamate-Cysteine Ligase; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; C495636:Nfe2l2 protein, mouse; C076944:salvianolic acid B; D053630:Depsides
Acetaminophen hepatotoxicity; Nrf2; PI3K; PKC; Phase II enzyme; Salvianolic acid B (SalB)