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PAPSS2 ablation prevents acetaminophen‐induced hepatotoxicity in mice
Author(s) -
Xu Pengfei,
Wang Pengcheng,
Xi Yue,
An Yunqi,
Xu Meishu,
Ren Songrong,
Ma Xiaochao,
Xie Wen
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01887
Subject(s) - acetaminophen , sulfation , detoxification (alternative medicine) , pharmacology , chemistry , liver injury , enzyme , antioxidant , biochemistry , medicine , alternative medicine , pathology
Sulfate plays an essential role in numerous biochemical and cellular processes in mammalian physiology. The PAPS synthase 2 (PAPSS2) is the primary enzyme to synthesize 3'‐phosphoadenosine 5'‐phosphosulfate (PAPS), which is the universal sulfonate donor for all sulfonation reactions in mammals. Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the United States, and sulfation is widely believed to contribute to the detoxification of many drugs including APAP. The goal of this study is to determine whether PAPSS2 plays a role in APAP‐induced hepatotoxicity. Surprisingly, we found the PAPSS2 knockout mice were protected from APAP‐induced hepatotoxicity, and this protection was accompanied by increased antioxidant ability through the activation Nrf2‐Keap1 and p53 pathways. The hepatoprotective effect of PAPSS2 ablation was abolished when p53 was knocked down. In summary, we have uncovered a unique role of PAPSS2 in APAP‐induced hepatotoxicity. Support or Funding Information This work was supported in part by National Institutes of Health Grants DK083952, ES023438