Nrf2-mediated liver protection by sauchinone, an antioxidant lignan, from acetaminophen toxicity through the PKC Delta d-GSK3 Delta b pathway

• Published in: British journal of pharmacology 2011-08, Vol.163 (8), p.1653-1665
• Main Authors: Kay, Hee Yeon, Kim, Young Woo, Ryu, Da Hye, Sung, Sang Hyun, Hwang, Se Jin, Kim, Sang Geon
• Format: Article
• Language: English
• ISSN: 1476-5381
• DOI: 10.1111/j.1476-5381.2010.01095.x

Keywords: sauchinone; acetaminophen; Nrf2; PKC Delta *d; GSK3 Delta *b BACKGROUND AND PURPOSE Sauchinone, an antioxidant lignan, protects hepatocytes from iron-induced toxicity. This study investigated the protective effects of sauchinone against acetaminophen (APAP)-induced toxicity in the liver and the role of nuclear factor erythroid-2-related factor-2 (Nrf2) in this effect. EXPERIMENTAL APPROACH Blood biochemistry and histopathology were assessed in mice treated with APAP or APAP + sauchinone. The levels of mRNA and protein were measured using real-time PCR assays and immunoblottings. KEY RESULTS Sauchinone ameliorated liver injury caused by a high dose of APAP. This effect was prevented by a deficiency of Nrf2. Sauchinone treatment induced modifier subunit of glutamate-cysteine ligase, NAD(P)H:quinone oxidoreductase-1 (NQO1) and heat shock protein 32 in the liver, which was abolished by Nrf2 deficiency. In a hepatocyte model, sauchinone activated Nrf2, as evidenced by the increased nuclear accumulation of Nrf2, the induction of NQO1-antioxidant response element reporter gene, and glutamate-cysteine ligase and NQO1 protein induction, which contributed to the restoration of hepatic glutathione content. Consistently, treatment of sauchinone enhanced Nrf2 phosphorylation with a reciprocal decrease in its interaction with Kelch-like ECH-associated protein-1. Intriguingly, sauchinone activated protein kinase C- Delta *d (PKC Delta *d), which led to Nrf2 phosphorylation. In addition, it increased the inhibitory phosphorylation of glycogen synthase kinase-3 Delta *b (GSK3 Delta *b), derepressing Nrf2 activity, which was supported by the reversal of sauchinone's activation of Nrf2 by an activated mutant of GSK3 Delta *b. Moreover, phosphorylation of GSK3 Delta *b by sauchinone depended on PKC Delta *d activation. CONCLUSION AND IMPLICATIONS Our results demonstrate that sauchinone protects the liver from APAP-induced toxicity by activating Nrf2, and this effect is mediated by PKC Delta *d activation, which induces inhibitory phosphorylation of GSK3 Delta *b.