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)

Polymorphonuclear leucocyte function was investigated in twenty patients with alcoholic cirrhosis and three patients with cryptogenic cirrhosis. Bacterial ingestion, oxygen-dependent bactericidal capacity, and chemotactic response were measured. Serum dependent abnormalities were common; they included deficiencies of ingestion and of all subsequent oxygen-dependent metabolic events (three patients), all oxygen-dependent metabolic events (one patient), cytochrome c reduction and iodination deficiencies (six patients), isolated cytochrome c reduction deficiency (ten patients), and chemotactic deficiencies (fourteen out of eighteen patients). Serum-independent abnormalities were much less common; they included increased ingestion rate (four patients), decreased stimulated reduction of nitroblue tetrazolium (three patients), and decreased myeloperoxidase content (eight patients). Polymorphonuclear leucocyte abnormalities are frequent in cirrhosis and may account in part for increased susceptibility to infection in that disease.
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PMID:Blood polymorphonuclear dysfunction in patients with alcoholic cirrhosis. 41 78

In erythropoietic protoporphyria, accumulation of protoporphyrin has been found in various tissues and liver cirrhosis occurs frequently in this disease, probably due to toxic dark effects of protoporphyrin. We have studied the effect of porphyrins on various enzymic functions in rat liver microsomes. Incubation of microsomes with protoporphyrin resulted in a concentration-dependent inhibition of the oxidation of 7-ethoxycoumarin and aminopyrine by the cytochrome P-450 system. Kinetic analysis showed a decrease in Vmax., whereas the Km was not affected (non-competitive inhibition). Furthermore, reduction of cytochrome c by the NADPH-cytochrome P-450 reductase and by the NADH-cytochrome b5 reductase was inhibited. However, the activity of the reductases was only affected when the microsomes were pre-incubated with protoporphyrin, and it was found that the inhibition was dependent on the duration of the pre-incubation. Kinetic analysis again revealed non-competitive inhibition. When these experiments were repeated with uroporphyrin, no inhibition could be observed. With Stern-Volmer plots it was demonstrated that this was most likely caused by the localization of the porphyrins: protoporphyrin is localized in the membrane, whereas uroporphyrin remains in solution. From these results it is concluded that accumulation of protoporphyrin in the liver may markedly affect the cytochrome P-450 system and thus its detoxification function.
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PMID:Toxic dark effects of protoporphyrin on the cytochrome P-450 system in rat liver microsomes. 133 95

Cytochrome c oxidase activity, measured as Vmax (nanomoles of cytochrome c oxidized per second per milligram of protein) and Michaelis constant (Km) (micromoles per liter), was measured spectrophotometrically in human liver specimens obtained by needle biopsy from 43 patients. In 16 normal livers, the Vmax and Km values ranged from 1.26 to 2.25 nmol/s per milligram of protein and from 2.78 to 3.95 mumol/L, respectively. In 27 patients with liver cirrhosis or chronic hepatitis, these values ranged from 1.60 to 3.80 nmol/s per milligram of protein and from 2.80 to 6.50 mumol/L, respectively. Patients with Vmax above 2.5 nmol/s per milligram of protein or Km above 5.0 mumol/L had a high incidence of postoperative complications even after minor hepatic resection. By contrast, even patients with liver cirrhosis or chronic hepatitis could tolerate major hepatic resection as long as their Vmax and Km values were within the normal range. These findings indicate that the cytochrome c oxidase activity in liver specimens can serve as a prognostic sign in hepatic resection even in patients with liver cirrhosis or chronic hepatitis.
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PMID:Cytochrome c oxidase activity in human liver specimens. An index of prognosis for hepatic resection. 215 79

The effects of lentinan on enzyme induced lipid peroxidation, xanthine-xanthine oxidase-induced cytochrome c reduction, and on the superoxide-dismutase (SOD) enzyme activity and expression of human lymphocytes and erythrtocytes were studied. Lentinan in low concentration decreased SOD activity of lymphocytes and erythrocytes from healthy subjects. In higher concentration (10 micrograms/ml) lentinan increased the pathologically low SOD activity of erythrocytes and lymphocytes of patients with cirrhosis of the liver. No significant antioxidant (free radical scavenger) effect has been observed in NADPH-induced and Fe3+-stimulated lipid peroxidation and in xanthine-xanthine oxidase system.
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PMID:Effect of lentinan on superoxide dismutase enzyme activity in vitro. 254 63

In the liver of 12 patients with porphyria cutanea tarda (PCT) the following parameters were measured: protein-content, NADPH-cytochrome c-reductase, 7-ethoxycoumarin-deethylase. The results were compared with the findings of patients with chronic liver disease (chronic hepatitis or cirrhosis) and patients without any liver affection. In addition the in vitro inhibition of 7-ethoxycoumarin-deethylase by metyrapone (phenobarbital induced cytochrome P-450) or naphthoflavone (benzo[a]pyrene induced cytochrome P-448) was estimated. No differences were found between the various groups. It is assumed that the induction of the mixed function monooxygenases is not an essential condition for the development or the persistence of the human porphyria cutanea tarda.
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PMID:[Cytochrome P-450 dependent enzymatic activity in the liver of patients with porphyria cutanea tarda (author's transl)]. 677 32

Persistent hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Numerous viruses have been reported to escape from apoptotic mechanism to maintain persistent infection. In the present study, we characterized the effect of HCV proteins on the Fas signal using HCV transgenic mice, which expressed core, E1, E2, and NS2 proteins, regulated by the Cre/loxP switching system. The transgene expression of HCV transgenic mice caused resistance to Fas antibody stimulated lethality. Apoptotic cell death in the liver of HCV protein expressing mice was significantly reduced compared with nonexpressing mice. Histopathological analysis and DNA fragmentation analysis revealed that the HCV proteins suppressed Fas-mediated apoptotic cell death. To identify the target pathway of HCV proteins, we characterized caspase activity. The activation of caspase-9 and -3/7 but not caspase-8 was inhibited by HCV proteins. Cytochrome c release from mitochondria was inhibited in HCV protein expressing mice. These results indicated that the expression of HCV proteins may directly or indirectly inhibit Fas-mediated apoptosis and death in mice by repressing the release of cytochrome c from mitochondria, thereby suppressing caspase-9 and -3/7 activation. These results suggest that HCV may cause persistent infection, as a result of suppression of Fas-mediated cell death.
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PMID:Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins. 1127 24

S-adenosylmethionine (AdoMet) is an essential compound in cellular transmethylation reactions and a precursor of polyamine and glutathione synthesis in the liver. In liver injury, the synthesis of AdoMet is impaired and its availability limited. AdoMet administration attenuates experimental liver damage, improves survival of alcoholic patients with cirrhosis, and prevents experimental hepatocarcinogenesis. Apoptosis contributes to different liver injuries, many of which are protected by AdoMet. The mechanism of AdoMet's hepatoprotective and chemopreventive effects are largely unknown. The effect of AdoMet on okadaic acid (OA)-induced apoptosis was evaluated using primary cultures of rat hepatocytes and human hepatoma cell lines. AdoMet protected rat hepatocytes from OA-induced apoptosis dose dependently. It attenuated mitochondrial cytochrome c release, caspase 3 activation, and poly(ADP-ribose) polymerase cleavage. These effects were independent from AdoMet-dependent glutathione synthesis, and mimicked by 5'-methylthioadenosine (MTA), which is derived from AdoMet. Interestingly, AdoMet and MTA did not protect HuH7 cells from OA-induced apoptosis; conversely both compounds behaved as proapoptotic agents. AdoMet's proapoptotic effect was dose dependent and observed also in HepG2 cells. In conclusion, AdoMet exerts opposing effects on apoptosis in normal versus transformed hepatocytes that could be mediated through its conversion to MTA. These effects may participate in the hepatoprotective and chemopreventive properties of this safe and well-tolerated drug.
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PMID:S-adenosylmethionine and methylthioadenosine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells. 1182 99

Whereas ch/ch wild-type mice and ch/14CoS heterozygotes are viable, 14CoS/14CoS mice homozygous for a 3800 kb deletion on chromosome 7 die during the first day postpartum. Death is caused by disruption of the fumarylacetoacetate hydrolase (Fah) gene; absence of FAH, final enzyme in the tyrosine catabolism pathway, leads to accumulation of reactive electrophilic intermediates. In this study, we kept 14CoS/14CoS mice alive for 60 d with oral 2-(2-nitro-4-trifluoromethyl-benzyol)-1,3-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, second enzyme in the tyrosine catabolic pathway. The 70% of NTBC-treated 14CoS/14CoS mice that survived 60 d showed poor growth and developed corneal opacities, compared with ch/14CoS littermates; NTBC-rescued Fah(-/-) knockout mice did not show growth retardation or ocular toxicity. NTBC-rescued 14CoS/14CoS mice also exhibited a striking oxidative stress response in liver and kidney, as measured by lower GSH levels and mRNA induction of four genes: glutamate cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, NAD(P)H:quinone oxidoreductase (Nqo1), and heme oxygenase-1 (Hmox1). Withdrawal of NTBC for 24-48 h from rescued adult 14CoS/14CoS mice resulted in severe apoptosis of the liver, detected histologically and by cytochrome c release from the mitochondria, increased caspase 3-like activity, and further decreases in GSH content. In kidney, proximal tubular epithelial cells were abnormal. Human hereditary tyrosinemia type I (HT1), caused by mutations in the FAH gene, is an autosomal recessive disorder in which the patient usually dies of liver fibrosis and cirrhosis during early childhood; NTBC treatment is known to prolong HT1 children's lives-although liver fibrosis, cirrhosis, hepatocarcinoma, and corneal opacities sometimes occur. The mouse data in the present study are consistent with the possibility that endogenous oxidative stress-induced apoptosis may be the underlying cause of liver pathology seen in NTBC-treated HT1 patients.
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PMID:Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress. 1289 38

Liver homeostasis is achieved by the removal of diseased and damaged hepatocytes and their coordinated replacement to maintain a constant liver cell mass. Cirrhosis, viral hepatitis, and toxic drug effects can all trigger apoptosis in the liver as a means of removing the unwanted cells, and the Fas "death receptor" pathway comprises a major physiological mechanism by which this occurs. The susceptibility to Fas-mediated apoptosis is, in part, a function of the hepatocyte's proteome. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to influence apoptosis, conceivably by regulating the expression of genes involved in apoptotic signaling. In this article, we present evidence demonstrating that AhR expression and function promote apoptosis in liver cells in response to Fas stimulation. Reintroduction of the AhR into the AhR-negative BP8 hepatoma cells as well as into primary hepatocytes from AhR knockout mice increases the magnitude of cell death in response to Fas ligand. Enhanced apoptosis correlates with increased caspase activity and mitochondrial cytochrome c release but not with the expression of several Bcl-2 family proteins. In vivo studies showed that in contrast to wild-type mice, AhR knockout mice are protected from the lethal effects of the anti-Fas Jo2 antibody. Moreover, down-regulation of the aryl hydrocarbon receptor nuclear translocator protein in vivo by adenovirus-mediated RNA interference to suppress AhR activity provided wild-type mice partial protection from Jo2-induced lethality.
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PMID:The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. 1555 Jun 80

Liver cirrhosis is often preceded by overt signs of hepatitis, including parenchymal cell inflammation and infiltration of polymorphonuclear (PMN) leukocytes. Activated PMNs release both reactive oxygen species and reactive halogen species, including hypochlorous acid (HOCl), which are known to be significantly cytotoxic due to their oxidizing potential. Because the role of mitochondria in the hepatotoxicity attributed to HOCl has not been elucidated, we investigated the effects of HOCl on mitochondrial function in the human hepatoma HepG2 cell line, human fetal liver cells, and isolated rat liver mitochondria. We show here that HOCl induced mitochondrial dysfunction, and apoptosis was dependent on the induction of the mitochondrial permeability transition (MPT), because HOCl induced mitochondrial swelling and collapse of the mitochondrial membrane potential with the concomitant release of cytochrome c. These biochemical events were inhibited by the classical MPT inhibitor cyclosporin A (CSA). Cell death induced by HOCl exhibited several classical hallmarks of apoptosis, including annexin V labeling, caspase activation, chromatin condensation, and cell body shrinkage. The induction of apoptosis by HOCl was further supported by the finding that CSA and caspase inhibitors prevented cell death. For the first time, these results show that HOCl activates the MPT, which leads to the induction of apoptosis and provides a novel insight into the mechanisms of HOCl-mediated cell death at sites of chronic inflammation.
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PMID:Hypochlorous acid-mediated mitochondrial dysfunction and apoptosis in human hepatoma HepG2 and human fetal liver cells: role of mitochondrial permeability transition. 1591 86


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