Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methionine adenosyltransferase (MAT) is an ubiquitous enzyme that catalyzes the synthesis of S-adenosylmethionine from methionine and ATP. In mammals, there are two genes coding for MAT, one expressed exclusively in the liver and a second enzyme present in all tissues. Molecular studies indicate that liver MAT exists in two forms: as a homodimer and as a homotetramer of the same oligomeric subunit. The liver-specific isoenzymes are inhibited in human liver cirrhosis, and this is the cause of the abnormal metabolism of methionine in these subjects.
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PMID:S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. 917 57

Formation of bile requires the coordinated function of two epithelial cell types: hepatocytes, that are responsible for secretion of the major osmolytes and biliary constituents and cholangiocytes that regulate the fluidity and alkalinity of bile through secretion of osmolytes such as Cl- and HCO3- Studies in isolated cholangiocyte preparations have elucidated the basic transport mechanisms involved in constitutive and stimulated secretory activities in the biliary epithelium. Basolateral Na+/H+ exchanger and Na+:HCO3- symporter mediate HCO3- uptake, while an apical cAMP-activated Cl-/HCO3- exchanger secretes bicarbonate into the lumen. Cholangiocytes also possess a cAMP-stimulated Cl- conductance (CFTR) and a Ca-activated Cl- channel, both likely located at the apical membrane. Cholangiocyte secretory functions are regulated by a complex network of hormones mainly acting via the cAMP system. In addition, recent data indicate that part of the regulation of ductular secretion may take place at the apical membrane of the cholangiocyte through factors present into the bile, such as ATP, bile acids and glutathione. Primary damage to the biliary epithelium is the cause of several chronic cholestatic disorders (cholangiopathies). From a pathophysiological point of view, common to all cholangiopathies is the coexistance of cholangiocyte death and proliferation and various degrees of portal inflammation and fibrosis. Cholestasis dominates the clinical picture and, pathophysiologically, may initiate or worsen the process. Alterations in biliary electrolyte transport could contribute to the pathogenesis of cholestasis in primary bile duct diseases. Cystic Fibrosis-related liver disease represents an example of biliary cirrhosis secondary to a derangement of cholangiocyte ion transport. Most primary cholangiopaties recognize an immune-mediated pathogenesis. Cytokines, chemokines, and proinflammatory mediators released in the portal spaces or produced by the cholangiocyte itself, likely activate fibrogenesis, stimulate apoptotic and proliferative responses, and alter the transport functions of the epithelium.
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PMID:Transport systems in cholangiocytes: their role in bile formation and cholestasis. 962 63

We studied the influence of intermittent ischemic injury on thioacetamide-induced liver cirrhosis in rats. Wistar rats were divided into group A, intermittent ischemic injury to liver cirrhosis, and group B, continuous ischemic injury to liver cirrhosis. Total ischemic time was 60 min in both groups. In group A, ischemic injury consisted of a repetition 4 times of 15 min ischemia and 5 min reperfusion. The ATP level of the liver was measured before ischemia, before reperfusion, and 60 min after reperfusion. Bile was collected to determine bile flow rate. The ATP level in the liver tissue 60 min after reperfusion was significantly (p < 0.05) higher in group A than in group B. The ATP level immediately before reperfusion was also significantly (p < 0.05) higher in group A than in group B. The survival rate 1 week after ischemic injury and bile flow rate 60 min after reperfusion were significantly (p < 0.01) higher in group A compared with those in group B. The energy level was much higher in intermittent ischemic injury than in continuous ischemic injury immediately before reperfusion and after reperfusion. Survival rate and bile flow rate were higher in intermittent ischemic injury than in continuous ischemic injury. Therefore it suggests that the viability of the liver was maintained better in intermittent ischemic injury than in continuous ischemic injury.
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PMID:Influence of intermittent ischemia on thioacetamide-induced rat liver cirrhosis. 962 15

NMR spectroscopy was used to examine hepatic metabolism in cirrhosis with a particular focus on markers of functional cellular hypoxia. (31)P and (1)H NMR spectra were obtained from liver extracts from control rats and from rats with carbon tetrachloride-induced cirrhosis. A decrease of 34% in total phosphorus content was observed in cirrhotic rats, parallelling a reduction of 40% in hepatocyte mass as determined by morphometric analysis. Hypoxia appeared to be present in cirrhotic rats, as evidenced by increased inorganic phosphate levels, decreased ATP levels, decreased ATP:ADP ratios (1.72 +/- 0.40 vs 2.48 +/- 0.50, p < 0.01), and increased inorganic phosphate:ATP ratios (2.77 +/- 0.48 vs 1.62 +/- 0.24, p < 0.00001). When expressed as a percentage of the total phosphorus content, higher levels of phosphoethanolamine and lower levels of NAD and glycerophosphoethanolamine were detected in cirrhotic rats. Cirrhotic rats also had increased phosphomonoester:phosphodiester ratios (5.73 +/- 2.88 vs 2.53 +/- 0.52, p < 0.01). These findings are indicative of extensive changes in cellular metabolism in the cirrhotic liver, with many findings attributable to the presence of intracellular hypoxia.
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PMID:31P and 1H NMR spectroscopic studies of liver extracts of carbon tetrachloride-treated rats. 1051 22

The oxygen limitation hypothesis states that hepatocyte hypoxia is the mechanism determining metabolic restriction in the cirrhotic liver. Therefore we studied markers of hepatocyte energy state and cellular hypoxia in livers of normal and cirrhotic rats before and after oxygen supplementation. Rats with carbon tetrachloride-induced cirrhosis and procedural control rats were exposed to either room air or a hyperoxic gas mixture for 1 h immediately before freeze clamping and perchloric acid extraction of liver tissue. Extracts were assessed by (31)P NMR and enzymatic assays. Livers from cirrhotic rats breathing room air showed a reduced ratio of ATP/ADP, an increased ratio of inorganic phosphate/ATP, and a trend toward an increased ratio of lactate/pyruvate compared with procedural control livers (ATP/ADP 1.73 +/- 0.35 versus 2.68 +/- 0.61, P <.05; P(i)/ATP 2.74 +/- 0.48 versus 1.56 +/- 0.26, P <.05; lactate/pyruvate 29.3 +/- 6.4 versus 22.5 +/- 7.4, P =.18). After supplementation with oxygen for 1 h, these ratios in cirrhotic livers approached control values. A variety of other metabolic markers affected by cirrhosis showed variable trends toward normal in response to oxygen supplementation, whereas minor trends toward an increase in ATP levels in control animals suggest the possibility of marginal oxygen limitation in normal livers. The data are consistent with the hypothesis that hepatocytes in cirrhotic livers have normal metabolic capacity but are constrained by a deficit in oxygen supply. Interventions aimed at increasing oxygen supply to the liver may have both short- and long-term therapeutic value in the management of cirrhosis.
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PMID:Acute oxygen supplementation restores markers of hepatocyte energy status and hypoxia in cirrhotic rats. 1077 39

The effects of bile acids on intracellular Ca(2+) concentration [Ca(2+)](i) and nitric oxide production were investigated in vascular endothelial cells. Whole-cell patch clamp techniques and fluorescence measurements of [Ca(2+)](i) were applied in vascular endothelial cells obtained from human umbilical and calf aortic endothelial cells. Nitric oxide released was determined by measuring the concentration of NO(2)(-). Deoxycholic acid, chenodeoxycholic acid and the taurine conjugates increased [Ca(2+)](i) concentration-dependently, while cholic acid showed no significant effect. These effects resulted from the first mobilization of Ca(2+) from an inositol 1,4,5-triphosphate (IP(3))-sensitive store, which was released by ATP, then followed by Ca(2+) influx. Both bile acids and ATP induced the activation of Ca(2+)-dependent K(+) current. Oscillations of [Ca(2+)](i) were occasionally monitored with the Ca(2+)-dependent K(+) current in voltage-clamped cells and Ca(2+) measurements of single cells. The intracellular perfusion of heparin completely abolished the ATP effect, but failed to inhibit the bile acid effect. Deoxycholic acid and chenodeoxycholic acid enhanced NO(2)(-) production concentration-dependently, while cholic acid did not enhance it. The bile acids-induced nitric oxide production was suppressed by N(G)-nitro-L-arginine methyl ester, exclusion of extracellular Ca(2+) or N-(6-aminohexyl)-5-chloro-l-naphthalenesulphonamide hydrochloride (W-7) and calmidazolium, calmodulin inhibitors. These results provide novel evidence showing that bile acids increase [Ca(2+)](i) and subsequently nitric oxide production in vascular endothelial cells. The nitric oxide production induced by bile acids may be involved in the pathogenesis of circulatory abnormalities in liver diseases including cirrhosis.
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PMID:Bile acids increase intracellular Ca(2+) concentration and nitric oxide production in vascular endothelial cells. 1092 45

Hepatocyte injury and necrosis from many causes may result in pediatric liver disease. Influenced by other cell types in the liver, by its unique vascular arrangements, by lobular zonation, and by contributory effects of sepsis, reactive oxygen species and disordered hepatic architecture, the hepatocyte is prone to injury from exogenous toxins, from inborn errors of metabolism, from hepatotrophic viruses, and from immune mechanisms. Experimental studies on cultured hepatocytes or animal models must be interpreted with caution. Having discussed general concepts, this review describes immune mechanisms of liver injury, as seen in autoimmune hepatitis, hepatitis B and C infection, the anticonvulsant hypersensitivity syndrome, and autoimmune polyendocrinopathy. Of the monogenic disorders causing significant liver injury in childhood, alpha-1 antitrypsin deficiency and Niemann-Pick C disease demonstrate the effect of endoplasmic or endosomal retention of macromolecules. Tyrosinemia illustrates how understanding the biochemical defect leads to understanding cell injury, extrahepatic porphyric effects, oncogenesis, pharmacological intervention, and possible stem cell therapy. Pathogenesis of cirrhosis in galactosemia remains incompletely understood. In hereditary fructose intolerance, phosphate sequestration causes ATP depletion. Recent information about mitochondrial disease, NASH, disorders of glycosylation, Wilson's disease, and the progressive familial intrahepatic cholestases is discussed.
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PMID:Mechanisms of liver injury relevant to pediatric hepatology. 1189 Feb 7

In addition to the usual associations with insulin resistance, type 2 diabetes, central obesity, and hypertriglyceridemia, nonalcoholic steatohepatitis (NASH) has been associated with several drugs and toxins. However, drug-induced liver disease is a relatively uncommon cause of steatohepatitis. The term drug-induced steatohepatitis is preferred when the association appears to result from a direct toxic effect of the drug on the liver. For some agents implicated as causing cirrhosis or fatty liver disorders, the association may be coincidental because NASH is a common component of the insulin resistance (or metabolic) syndrome. In other instances, corticosteroids, tamoxifen, and estrogens may precipitate NASH in predisposed persons by exacerbating insulin resistance, central obesity, diabetes, and hypertriglyceridemia, and methotrexate may worsen hepatic fibrosis in NASH. Drug-induced steatohepatitis is associated with prolonged therapy (more than 6 months) and possibly drug accumulation, which in the case of perhexiline maleate is favored by a genetic polymorphism of CYP2D6 that leads to slow perhexiline oxidation. The toxic mechanism appears to involve mitochondrial injury, which causes steatosis because of impaired beta-oxidation of fatty acids, and leads to generation of reactive oxygen species and ATP depletion. Thus, drug-induced steatohepatitis may provide clues to injurious events in the more common metabolic forms of NASH. A clinical feature of some types of drug-induced steatohepatitis is progression after discontinuation of the causative agent. It follows that early recognition of hepatotoxicity is crucial to prevent the development of severer forms of liver disease and improve the clinical outcome.
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PMID:Drugs and steatohepatitis. 1201 49

The canalicular multidrug resistance protein 2 (MRP2; gene symbol: ABCC2) mediates ATP-dependent biliary excretion of organic anions such as bilirubin diglucuronide, glutathione conjugates and sulfated and glucuronidated bile salts. In chronic cholestatic liver diseases, the biliary excretion of cholephilic organic anions is impaired. While the underlying transport defects have been studied in rat models of cholestasis, little is known about the molecular basis of impaired organic anion excretion in human cholestatic liver disease. Our aim, therefore, was to analyze expression of MRP2 in patients with primary biliary cirrhosis (PBC), a chronic cholestatic liver disease characterized by progressive destruction of small intrahepatic bile ducts. Four patients with PBC stages III (n=1) and IV (n=3) were compared with three non-cholestatic patients with alcoholic liver disease, idiopathic liver cirrhosis and cirrhosis from chronic hepatitis C. Immunohistochemistry was performed on paraffin-embedded tissue slides using a monoclonal antibody to MRP2. MRP2 was detected at the canalicular hepatocyte membrane of all patients. In two PBC patients (stages III and IV, respectively), the degree of immunostaining was comparable with controls, whereas in two other PBC patients with stage IV disease immunostaining was decreased. We conclude that MRP2 expression decreases with progressive cholestasis in PBC.
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PMID:Expression of the hepatocyte canalicular multidrug resistance protein (MRP2) in primary biliary cirrhosis. 1208 58

One of the features of liver cirrhosis is an abnormal metabolism of methionine--a characteristic that was described more than a half a century ago. Thus, after an oral load of methionine, the rate of clearance of this amino acid from the blood is markedly impaired in cirrhotic patients compared with that in control subjects. Almost 15 y ago we observed that the failure to metabolize methionine in cirrhosis was due to an abnormally low activity of the enzyme methionine adenosyltransferase (EC 2.5.1.6). This enzyme converts methionine, in the presence of ATP, to S-adenosyl-L-methionine (SAMe), the main biological methyl donor. Since then, it has been suspected that a deficiency in hepatic SAMe may contribute to the pathogenesis of the liver in cirrhosis. The studies reviewed here are consistent with this hypothesis.
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PMID:Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. 1241 1


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