Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory-gated proton magnetic resonance imaging was used to study the response of the rat liver in situ to bromobenzene, a classic hepatotoxicant. A localized region of high proton signal intensity in the perihilar region of the liver was seen 24-48 hr after an intraperitoneal injection of bromobenzene. Localized proton magnetic resonance spectra from within this region indicated that the increased proton signal intensity was not due to accumulation of fat in the liver, but primarily due to a longer T2 for the proton resonance of water. This is consistent with acute edema in this localized region. In vivo 31P magnetic resonance spectroscopy studies of the same rat livers in situ were performed. Spectroscopic conditions were determined whereby localized, quantitative 31P spectra could be obtained. Using these methods, 10 mmol/kg bromobenzene was found after 24 hr to cause a number of statistically significant (p less than 0.05) effects: a decrease in adenosine 5'-triphosphate levels from 4.1 +/- 0.5 to 3.0 +/- 0.5 mM, a decrease in phosphodiester levels from 11.3 +/- 0.9 to 9.3 +/- 0.7 mM and an increase in the phosphomonoesters from 3.0 +/- 0.4 to 5.5 +/- 1.2 mM (mean +/- standard deviation). High resolution in vitro 31P spectra of perchloric acid extracts of these rat livers showed that the increased phosphomonoester resonance was due to a selective 4.3-fold increase in phosphocholine. Thus, our in vivo and in vitro 31P magnetic resonance spectra are consistent with the hypothesis that a phosphatidylcholine-specific phospholipase C (generating phosphocholine and diacylglycerol) is activated during tissue damage. Both the imaging and spectroscopy results obtained with bromobenzene closely resemble CCl4-induced liver changes previously reported, and may reflect a generalized response of the liver to any acutely acting toxic chemical.
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PMID:Proton magnetic resonance imaging and phosphorus-31 magnetic resonance spectroscopy studies of bromobenzene-induced liver damage in the rat. 156 94

Carbon tetrachloride (CCl4) biotransformation and covalent binding was measured in 1000g liver fractions by determining the amount of 14CCl4 metabolites covalently bound to proteins and lipids at various (5-60 min) incubation times. Reactive intermediate binding to proteins and phospholipids peaked at 20 min, whereas CCl4 metabolites associated with neutral lipids (primarily diacylglycerol) were initially low (0-15 min) and then gradually increased from 20 to 60 min. The rise in labeled diacylglycerol was associated with a decrease in phospholipids containing covalently bound CCl4 metabolites, since CCl4 bioactivation increased phospholipase C (PLC) activity three- to fourfold. The major rise in PLC activity occurred after the plateau of CCl4 metabolite binding to cellular phospholipids. In contrast, when CCl4 bioactivation is absent, 0.5 mM CCl4 has little effect on PLC activity. At CCl4 concentrations of 1 mM and greater, the NADPH-dependent activation of PLC by CCl4 is reduced because CCl4 biotransformation is inhibited. Nevertheless, PLC is still activated by CCl4; however, PLC activation by high doses of CCl4 occurs by bioactivation-independent mechanisms. Therefore, there are two components of CCl4-induced PLC activation: one which is dependent on CCl4 biotransformation and one which is not. Under both conditions (+/- biotransformation), the activation of PLC may be a key event in CCl4 hepatotoxicity since PLC disrupts the functional and structural integrity of membranes by degrading membrane phospholipids.
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PMID:The influence of CCl4 biotransformation on the activation of rat liver phospholipase C in vitro. 342 Jun 12

Rats treated with a single 0.5 ml/kg dose (ip) of CCl4 exhibited a threefold increase in liver microsomal phospholipase C (PLC) activity that was enhanced by phenobarbital and diminished by metyrapone pretreatment, respectively. Hepatocytes and hepatocellular fractions exposed to 0.5 mM CCl4 in vitro also exhibited a rapid rise in PLC activity that was reduced by metyrapone. Metyrapone also reduced the CCl4-related increase in the PLC-mediated reductions in cellular phosphatidylcholine content. The influence of CCl4 biotransformation on the activation of liver cell PLC was assessed in vitro. Covalent binding of 14CCl4 metabolites to isolated hepatocyte proteins and lipids was linear through 20 min of incubation and then quickly plateaued. The association of CCl4 metabolites with cellular phospholipids was inhibited by metyrapone and preceded the CCl4-dependent rise in PLC activity. CCl4-mediated increases in PLC activity were rapid and preceded reductions in cell viability. The translocation of cytosolic PLC to membranes such as the endoplasmic reticulum may explain the rapid, metabolite-dependent activation of PLC.PLC activation by haloalkanes was proportional to dose and incubation time in the order of CBrCl3 greater than CCl4 greater than CHCl3 greater than CFCl3 which corresponds to the observed hepatotoxic potential of these agents in vivo and in vitro. Haloalkane-dependent increases in PLC activity were inhibited by metyrapone. These results suggest that chemical metabolites activate PLC in vitro and in vivo. Therefore, the activation of a PLC that degrades membrane phospholipids may represent an important step in the pathogenic scheme of chemical-mediated liver cell necrosis.
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PMID:The role of CCl4 biotransformation in the activation of hepatocyte phospholipase C in vivo and in vitro. 342 Jun 13

This study assessed the role of lipid peroxidation in the chemical-dependent activation of hepatic phospholipase C in vitro. Hepatocellular membranes (1000 X g) were incubated with sn-[1,3-14C] glycerol-3-P, ATP, CoA, palmitate, Ca2+, NaF and dithiothreitol to form membrane-bound, labeled phosphatidic acid. Membrane-associated phosphatidate was incubated (10-45 min) with 2 mM Fe2+SO4 or 5mM CCl4 in the presence or absence of various antioxidants. Membranes exposed to Fe2+SO4 displayed an antioxidant-sensitive, 20-fold increase in malonic dialdehyde (MDA) formation without measurable increase in phospholipase C activity. In contrast, membranes exposed to 5 mM CCl4 displayed an antioxidant-insensitive, 2-3-fold increase in phospholipase C activity without significant increase in MDA production. These results suggest that under these incubation conditions in vitro, the CCl4-dependent activation of hepatic phospholipase C is not regulated by nor dependent upon the peroxidation of membrane phospholipids.
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PMID:The role of lipid peroxidation in the chemical-dependent activation of hepatic phospholipase C in vitro. 356 5

Sprague-Dawley rats and cultured rat hepatocytes exposed to bromobenzene (BB) and carbon tetrachloride (CCl4) display rapid and significant increases and decreases in hepatic phospholipase C (PLC) and sn-glycerol-3-phosphate acyltransferase (GPAT) activities, respectively. Primary cultures of adult rat hepatocytes were used to determine if the BB- and CCl4-dependent alterations in phospholipid metabolism were related to the hepatotoxicity of these agents. Cultured hepatocytes exposed to BB and CCl4 exhibited a rapid (1 to 5 min). PLC-mediated reduction (20 to 80%) in [32P]phosphatidylserine content. Other phospholipids were also reduced; however, phosphatidylserine was preferentially degraded by hepatotoxin-activated PLC. A time course of CCl4-and BB-induced cellular events showed that these agents (1) rapidly activate liver cell PLC activity; (2) accelerate 86Rb release; (3) decrease GPAT acyltransferase activity; and (4) cause a release of intracellular enzymes (GOT and GPT). All of these BB- and CCl4-mediated effects on the functional integrity of liver cells were blocked or reduced by agents (EDTA and chlorpromazine) that reduce the BB- and CCl4-dependent rise in PLC activity. Therefore, BB- and CCl4-dependent alterations in the functional and structural integrity of liver cells may be a result of accelerated phospholipid degradation and a corresponding inability of the cell to repair injured membranes by generating new phospholipids.
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PMID:The role of phospholipid metabolism in bromobenzene- and carbon tetrachloride-dependent hepatocyte injury. 647 78

A fibrogenic factor which stimulates collagen production without cell proliferation of rat skin fibroblast cultures was isolated from CCl4-damaged rat liver. (1) The factor was isolated from saline extracts of CCl4-induced fibrotic rat liver and fractionated by Sephadex G-50S gel filtration and DEAE-cellulose chromatography. The original extract produced a 6-fold increase in collagen synthesis and the active factor eluted from gel filtration columns in a region corresponding to 5000 daltons. (2) The active factor was destroyed by heat (57 degrees C, 30 min), phospholipase C digestion, but was insensitive to proteolytic enzymes or phospholipase A. Chemical analysis of the partially purified factor revealed relatively high quantities of phosphorus (3%) and low quantities of protein (13.3%), neutral sugar (1.9%) and uronic acid (4.9%). The possibility of this component being a complex phospholipid containing polypeptide is suggested. (3) Fibrogenic properties of the isolated factor was enhanced by apparent oxidation in air, to a more active, yet insoluble complex. Attempts to solubilize the oxidized product completely destroyed its biological activity.
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PMID:Isolation and characterization of a fibrogenic factor from CCl(4)-damaged rat liver. 711 58