ABSTRACT
Rifampicin (RFP) has demonstrated potent antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver intensively limit the clinical usage of the drug. Deacetylation greatly reduces the toxicity of RFP but also retains its curative activity. Here, we found that Krüppel-like factor 15 (KLF15) repressed the expression of the major RFP detoxification enzyme Cyp3a11 in mice via both direct and indirect mechanisms. Knockout of hepatocyte KLF15 induced the expression of Cyp3a11 and robustly attenuated the hepatotoxicity of RFP in mice. In contrast, overexpression of hepatic KLF15 exacerbated RFP-induced liver injury as well as mortality. More importantly, the suppression of hepatic KLF15 expression strikingly restored liver functions in mice even after being pretreated with overdosed RFP. Therefore, this study identified the KLF15-Cyp3a11 axis as a novel regulatory pathway that may play an essential role in the detoxification of RFP and associated liver injury. SIGNIFICANCE STATEMENT: Rifampicin has demonstrated antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver limit the clinical usage of the drug. Permanent depletion and transient inhibition of hepatic KLF15 expression significantly induced the expression of Cyp3a11 and robustly attenuated mouse hepatotoxicity induced by RFP. Overall, our studies show the KLF15-Cyp3a11 axis was identified as a novel regulatory pathway that may play an essential role in the detoxification of RFP and associated liver injury.
Subject(s)
Chemical and Drug Induced Liver Injury , Cytochrome P-450 CYP3A , Kruppel-Like Transcription Factors , Liver , Mice, Inbred C57BL , Mice, Knockout , Rifampin , Animals , Rifampin/adverse effects , Rifampin/toxicity , Rifampin/pharmacology , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A/genetics , Kruppel-Like Transcription Factors/metabolism , Kruppel-Like Transcription Factors/genetics , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/metabolism , Mice , Male , Liver/drug effects , Liver/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Antibiotics, Antitubercular/adverse effects , Antibiotics, Antitubercular/pharmacology , Antibiotics, Antitubercular/toxicity , Membrane ProteinsABSTRACT
In situ flushing through surfactant-enhanced aquifer remediation (SEAR) technology has long been recognized as a promising technique for NAPL removal from contaminated aquifers. However, there have been few studies on the choice of surfactants. In this work, the interaction quantitative model between resonance light scattering intensity and the concentration of binary surfactant mixtures NP-10+SDBS and NP-10+CTAB was established, and the mechanism of binary surfactant interaction was explored through the model by the resonance light scattering method. The relationship between the model constants and NAPL solubilization was also investigated to better address the application of surfactants in practical NAPL-contaminated site remediation. The critical micelle concentrations (CMCs) of nonylphenol ethoxylate (NP-10), dodecyl benzene sulfonate (SDBS), hexadecyl trimethyl ammonium bromide (CTAB), and the binary surfactant mixtures were measured by resonance light scattering (RLS), which were consistent with those obtained from surface tension measurements. In all cases, the RLS signals exhibited similar variations with surfactant concentration. A quantitative calculation model based on the RLS measurement data was established, and the binding constants KNP-10+SDBS and KNP-10+CTAB were calculated to be 0.66 and 1.51 L·mmol-1, respectively, according to the equilibrium equations. The results showed that the binding constants have a significant positive correlation with NAPL solubilization.
Subject(s)
Environmental Restoration and Remediation , Groundwater , Water Pollutants, Chemical , Solubility , Surface-Active Agents/analysis , Water Pollutants, Chemical/analysisABSTRACT
Hepatic metabolism and elimination of endobiotics (for example, steroids, bile acids) and xenobiotics (for example, drugs, toxins) is essential for health. While the enzymatic (termed phase I-II) and transport machinery (termed phase III) controlling endobiotic and xenobiotic metabolism (EXM) is known, understanding of molecular nodal points that coordinate EXM function in physiology and disease remains incomplete. Here we show that the transcription factor Kruppel-like factor 15 (KLF15) regulates all three phases of the EXM system by direct and indirect pathways. Unbiased transcriptomic analyses coupled with validation studies in cells, human tissues, and animals, support direct transcriptional control of the EXM machinery by KLF15. Liver-specific deficiency of KLF15 (Li-KO) results in altered expression of numerous phase I-III targets, and renders animals resistant to the pathologic effects of bile acid and acetaminophen toxicity. Furthermore, Li-KO mice demonstrate enhanced degradation and elimination of endogenous steroid hormones, such as testosterone and glucocorticoid, resulting in reduced male fertility and blood glucose levels, respectively. Viral reconstitution of hepatic KLF15 expression in Li-KO mice reverses these phenotypes. Our observations identify a previously unappreciated transcriptional pathway regulating metabolism and elimination of endobiotics and xenobiotics.