Peroxiredoxin 6 mediates acetaminophen-induced hepatocyte death through JNK activation.

Dong Hun Lee, Young Suk Jung, Jaesuk Yun, Sang Bae Han, Yoon Seok Roh, Min Jong Song, Jin Tae Hong

Redox biology 2020 May

filter terms:

Acetaminophen (APAP) is one of the most frequently used drugs; however, its overdose leads to acute liver injury. Recently, studies have reported that the adduction of peroxiredoxin 6 (PRDX6), a member of the PRDX family of antioxidant enzymes, is associated with liver diseases. However, the role of PRDX6 in APAP-induced liver injury remains unclear. Here, we assessed both age-matched (about 12 weeks) PRDX6-overexpressing transgenic mice (PRDX6 mice) and wild type (WT) mice presenting acute liver injury induced by the intraperitoneal injection of APAP (500 mg/kg). Although PRDX6 is known as an antioxidant enzyme, PRDX6 mice unexpectedly demonstrated severe liver injury following APAP injection compared with WT mice. We observed that PRDX6 was hyperoxidized after APAP administration. Additionally, calcium-independent phospholipase A2 (iPLA2) activity and lysophosphatidylcholine (LPC) levels were markedly elevated in PRDX6 mice following APAP administration. Moreover, APAP-induced JNK phosphorylation was considerably increased in the liver of PRDX6 mice. MJ33, an inhibitor of PRDX6, attenuated APAP-induced liver injury both in WT and PRDX6 mice. Notably, MJ33 reduced the APAP-induced increase in JNK activation, iPLA2 activity, and LPC levels. Although SP600125, a JNK inhibitor, abolished APAP-induced liver injury, it failed to affect the APAP-induced hyperoxidation of PRDX6, iPLA2 activity, and LPC levels. These results suggested that PRDX6 was converted to the hyperoxidized form by the APAP-induced high concentration of hydrogen peroxides. In the liver, hyperoxidized PRDX6 induced cellular toxicity via JNK activation by enhancing iPLA2 activity and LPC levels; this mechanism appears to be a one-way cascade. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Dong Hun Lee, Young Suk Jung, Jaesuk Yun, Sang Bae Han, Yoon Seok Roh, Min Jong Song, Jin Tae Hong. Peroxiredoxin 6 mediates acetaminophen-induced hepatocyte death through JNK activation. Redox biology. 2020 May;32:101496