title: Rifampicin-induced injury in L02 cells is alleviated by 4-PBA via inhibition of the PERK-ATF4-CHOP pathway.
abstract: Endoplasmic reticulum (ER) stress-induced cell injury plays an important role in the development of drug-induced liver injury (DILI). However, little is known about the contribution of ER stress to RFP-induced cell injury. In our study, L02 cells were treated with different concentrations of RFP for different time intervals, and cell apoptosis, the survival rate, and the gene and protein expression of GRP78, PERK, ATF4, and CHOP were measured. Additionally, L02 cells were transfected with CHOP-siRNA or a CHOP-over expression plasmid or administered 4-PBA before treatment with RFP. We found that RFP increased the cell apoptosis rate, decreased cell survival, and increased the protein and gene levels of GRP78, PERK, ATF4 and CHOP in both a dose-dependent and a time-dependent manner. Following the transient knockdown of CHOP and treatment with RFP, cell apoptosis decreased and the survival rate increased. Overexpression of CHOP produced the opposite effects. Treatment with 4-PBA decreased the protein and gene expression of GRP78, PERK, ATF4 and CHOP. Additionally, 4-PBA reduced cell apoptosis, increased cell survival and decreased the level of ALT, AST, AKP, LDH and ATP in the cell culture supernatant. These results indicate that 4-PBA alleviates RFP-induced injury in L02 cells via inhibition of the PERK-ATF4-CHOP pathway.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Key Laboratory of Gastroenterology of Anhui Province, China; The First Affiliated Hospital of AUTCM, Anhui, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Key Laboratory of Gastroenterology of Anhui Province, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.affiliation: Basic Medical College of Anhui Medical University, Anhui, China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Key Laboratory of Gastroenterology of Anhui Province, China. Electronic address: xujm1017@163.com.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000904:Antibiotics, Antitubercular / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D010654:Phenylbutyrates / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D012293:Rifampin / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D000904:Antibiotics, Antitubercular; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D010654:Phenylbutyrates; D020011:Protective Agents; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C075773:4-phenylbutyric acid; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D012293:Rifampin
keywords: Cell injury; L02 cells; PERK-ATF4-CHOP pathway; Rifampicin