nitrophenols and Liver-Cirrhosis

Cell death, including apoptotic and non-apoptotic cell death, is frequently observed in liver disease. Upon activation of the mitochondrial apoptotic pathway, mitochondria release not only apoptogenic cytochrome c but also mitochondrial DNA (mtDNA) into the cytosol. The impact of DNase II, a lysosomal acid DNase that degrades mtDNA, on hepatocyte death remains unclear. Administration of ABT-737, a Bcl-xL inhibitor, upregulated DNase II activity in murine hepatocyte cell line BNL CL.2 cells and induced apoptosis. In cells treated with DNase II siRNA, ABT-737 led to accumulation of mtDNA in the cytosol and increased expression of interferon (IFN)-β and induction of propidium iodide (PI)-positive cells, in addition to apoptosis. Induced PI-positive cells were suppressed by RIP1 inhibitor, Necrostatin-1, but not by pan-caspase inhibitor, ZVAD-FMK, suggesting non-apoptotic cell death. Both the increase in IFN-β and the induction of non-apoptotic cell death were abolished by administering a TLR9 antagonist, ODN2088, or by the removal of mtDNA from cells with ethidium bromide. Hepatocyte-specific Mcl-1 knockout mice developed hepatocyte apoptosis accompanied by upregulated DNase II activity in their livers. Further knockout of DNase II induced IFN-β expression and RIP1-dependent non-apoptotic hepatocyte death, both of which were suppressed by the administration of ODN2088. Mice fed a high-fat diet (HFD), an obesity-associated fatty liver model, showed increased expression of IFN-β with suppression of DNase II activity in their livers and developed not only hepatocyte apoptosis but also non-apoptotic hepatocyte death. Hepatocyte-specific knockout of DNase II exacerbated HFD-induced non-apoptotic hepatocyte death and liver fibrosis. In conclusion, without DNase II, apoptotic stimulation on hepatocytes induces TLR9-dependent IFN-β production and RIP1-dependent non-apoptotic cell death originating from mtDNA. In fatty livers, DNase II activity is suppressed in contrast to simple inactivation of Bcl-xL or Mcl-1, and both apoptotic and non-apoptotic hepatocyte death can develop, leading to the progression of liver fibrosis.

Topics: Animals; Apoptosis; Biphenyl Compounds; Cell Death; Endodeoxyribonucleases; Enzyme Activation; GTPase-Activating Proteins; Hepatocytes; Interferon-beta; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Nitrophenols; Oligodeoxyribonucleotides; Piperazines; Signal Transduction; Sulfonamides; Toll-Like Receptor 9; Up-Regulation

The role of Kupffer cells in CCl(4)-induced fibrosis was investigated in vivo. Male Wistar rats were treated with phenobarbital and CCl(4) for 9 wk, and a group of rats were injected with the Kupffer cell toxicant gadolinium chloride (GdCl(3)) or were fed glycine, which inactivates Kupffer cells. After CCl(4) alone, the fibrosis score was 3.0 +/- 0.1 and collagen protein and mRNA expression were elevated, but GdCl(3) or glycine blunted these parameters. Glycine did not alter cytochrome P-450 2E1, making it unlikely that glycine affects CCl(4) metabolism. Treatment with GdCl(3) or glycine prevented CCl(4)-induced increases in transforming growth factor (TGF)-beta 1 protein levels and expression. CCl(4) treatment increased alpha-smooth muscle actin staining (score 3.0 +/- 0.2), whereas treatment with GdCl(3) and glycine during CCl(4) exposure blocked this effect (1.2 +/- 0.5); there was no staining with glycine treatment. These results support previous in vitro data and demonstrate that treatment of rats with the selective Kupffer cell toxicant GdCl(3) prevents stellate cell activation and the development of fibrosis.

Topics: Actins; Animals; Anti-Inflammatory Agents; Carbon Tetrachloride; Collagen; Endotoxins; Gadolinium; Gene Expression; Glycine; Kupffer Cells; Liver; Liver Cirrhosis; Male; Nitrophenols; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor beta

Phosphodiesterase I (EC 3.1.4.1) activity was detected in normal human blood serum. The enzyme is stable at laboratory temperature for three days, but is inactivated at pH less than 7. The pH for optimum activity increases with the substrate concentration (under the conditions used, from pH 9.0 to 10.2) and, conversely, the Km increases with pH and buffer concentration. The enzyme is inhibited by ethylenediaminetetraacetate but not by phosphate (0.1 mol/liter). We developed a simple quantitative method for its determination, based on hydrolysis of the p-nitrophenyl ester of thymidine 5'-monophosphate and subsequent measurement of the liberated p-nitrophenol at 400 nm in NaOH (0.1 mol/liter). Normal values (mean +/- 2 SD) were determined to be 33 +/- 6.4 U/liter. Preliminary studies indicate that phosphodiesterase I activity is greater than normal in serum of patients with necrotic changes in the liver or kidney or in cases of breast cancer, but not in that of patients with myocardial infarction, bone cancer, lung cancer, or chronic liver cirrhosis.

Topics: Alkaline Phosphatase; Bone Neoplasms; Breast Neoplasms; Edetic Acid; Female; Humans; Kinetics; Liver Cirrhosis; Lung Neoplasms; Male; Myocardial Infarction; Nitrophenols; Phosphates; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Thymine Nucleotides

Topics: Aniline Compounds; Animals; Body Weight; Carbon Tetrachloride; Cytochromes; Glucosephosphate Dehydrogenase; Hexobarbital; Liver; Liver Cirrhosis; NADP; Nitrophenols; Oxidoreductases; Rats; Time Factors

Topics: Alcoholism; Biliary Tract Diseases; Bilirubin; Biopsy, Needle; Chronic Disease; Coumarins; Glucuronates; Glucuronidase; Hemochromatosis; Hepatitis; Hepatitis A; Hexosyltransferases; Humans; Hyperbilirubinemia, Hereditary; Jaundice, Chronic Idiopathic; Liver; Liver Cirrhosis; Liver Diseases; Nitrophenols; Phenolphthaleins; Structure-Activity Relationship; Uridine Diphosphate Sugars

Topics: Animals; Benzoates; Carbon Tetrachloride Poisoning; Cytochromes; Enzyme Induction; Hepatectomy; Hexobarbital; Hydroxylation; Liver; Liver Cirrhosis; Liver Regeneration; Male; Nitrophenols; Oxidoreductases; Phenobarbital; Rats; Time Factors

Topics: Adult; Child; Diabetes Mellitus; Enzymes; Female; Genetics, Medical; Glucuronidase; Humans; Hydrogen-Ion Concentration; Lactones; Liver Cirrhosis; Male; Neoplasms; Nitrophenols; Phenolphthaleins; Pregnancy; Quinolines

Topics: Alkaline Phosphatase; Calcium; Cobalt; Histocytochemistry; Histological Techniques; Humans; Liver Cirrhosis; Nitrophenols; Organophosphorus Compounds; Phosphates; Research

Topics: Animals; Dinitrophenols; Glycogen; Glycogen Storage Disease; Liver Cirrhosis; Liver Cirrhosis, Experimental; Liver Glycogen; Nitrophenols