rifampin and 4-phenylbutyric-acid

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury, Chronic; Cytoprotection; Endoplasmic Reticulum Stress; Hep G2 Cells; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred ICR; Multidrug Resistance-Associated Protein 2; Phenylbutyrates; Protective Agents; Rifampin; Signal Transduction; Ubiquitination

In vitro studies have suggested that 4-phenylbutyrate (PBA) may rescue missense mutated proteins that underlie some forms of progressive familial intrahepatic cholestasis. Encouraging preliminary responses to 4-PBA have been reported in liver disease secondary to mutations in ABCB11 and ATP8B1. A 4-year-old boy with Byler disease was treated with 4-PBA in the forms of sodium PBA (5 months) and then glycerol PBA (7 months) as part of expanded access single patient protocols. During this therapy serum total bilirubin fell and his general well-being was reported to be improved, although total serum bile acids were not reduced. Discontinuation of rifampin therapy, which had been used to treat pruritus, resulted in reversible severe acute liver injury that was potentially the result of phenylacetate toxicity. Interactions between 4-PBA and cytochrome P450 enzymes should be considered in the use of this agent with special attention to potential phenylacetate toxicity.

Topics: Antineoplastic Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Child, Preschool; Cholestasis, Intrahepatic; Humans; Infant; Liver; Liver Function Tests; Male; Phenylacetates; Phenylbutyrates; Pruritus; Rifampin

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.

Topics: Activating Transcription Factor 4; Antibiotics, Antitubercular; Apoptosis; Cell Line; Cell Survival; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Phenylbutyrates; Protective Agents; Rifampin; Signal Transduction; Transcription Factor CHOP