title: Protective role of p53 in acetaminophen hepatotoxicity.
abstract: p53 is a tumor suppressor with a pro-death role in many conditions. However, in some contexts, evidence supports a pro-survival function. p53 has been shown to be activated in acetaminophen (APAP) toxicity but the impact of this on toxicity is uncertain. In the present study, we have found that p53 plays a protective role in APAP-induced liver injury. We inhibited p53 using three different approaches in mice, pifithrin-α (PFTα), knockdown of p53 expression with antisense oligonucleotide, and p53 knockout. Mice were treated with APAP (300mg/kg) i.p. and after 24h in all three conditions, the liver injury was more severe as reflected in higher ALT levels and great area of necrosis in histology of the liver. Conversely, a p53 activator, nutlin-3a, decreased the liver injury induced by APAP. In the p53 inhibition models, enhanced sustained JNK activation was seen in the early time course, while the JNK was suppressed with the p53 activator. In conclusion, p53 plays a novel protective role in APAP induced liver injury through inhibiting the activation of JNK, a key mediator in APAP-induced oxidative stress.
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
authors.forename: Yazhen
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Yin
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Yan
authors.affiliation: USC Research Center for Liver Disease, Keck School of Medicine of USC, Los Angeles, CA 90033, United States.
authors.forename: Sanda
authors.initials: S
authors.lastname: Win
authors.affiliation: USC Research Center for Liver Disease, Keck School of Medicine of USC, Los Angeles, CA 90033, United States.
authors.forename: Tin
authors.initials: T
authors.lastname: Aung Than
authors.affiliation: IONIS Pharmaceuticals, Inc., Carlsbad, CA 92010, United States.
authors.forename: Mariam
authors.initials: M
authors.lastname: Aghajan
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China. Electronic address: hongbo@cau.edu.cn.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.affiliation: USC Research Center for Liver Disease, Keck School of Medicine of USC, Los Angeles, CA 90033, United States. Electronic address: kaplowit@usc.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D052160:Benzothiazoles; D007093:Imidazoles; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D000082:Acetaminophen; D014050:Toluene; C482205:nutlin 3; C121565:pifithrin; D048670:MAP Kinase Kinase 4
keywords: Acetaminophen; JNK; Liver injury; P53