Changes in Distribution and Activity of Glutamine Synthetase in Carbon Tetrachloride–Induced Cirrhosis in the Rat: Potential Role in Hyperammonemia

Gebhardt, Rolf; Reichen, Jürg

doi:10.1002/hep.1840200320

Cited by 51 publications

(25 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Liver cirrhosis in animal models and man and hepatocellular carcinoma are associated with strongly reduced GS activity, followed by hyperammonemia (2,(55)(56)(57). In cirrhosis with collaterals, down-regulation of GS in scavenger cells may be related to portocaval shunting (3,58,59).…”

Section: Discussionmentioning

confidence: 99%

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Qvartskhava

Lang

Görg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Urea cycle defects and acute or chronic liver failure are linked to systemic hyperammonemia and often result in cerebral dysfunction and encephalopathy. Although an important role of the liver in ammonia metabolism is widely accepted, the role of ammonia metabolizing pathways in the liver for maintenance of whole-body ammonia homeostasis in vivo remains ill-defined. Here, we show by generation of liver-specific Gln synthetase (GS)-deficient mice that GS in the liver is critically involved in systemic ammonia homeostasis in vivo. Hepatic deletion of GS triggered systemic hyperammonemia, which was associated with cerebral oxidative stress as indicated by increased levels of oxidized RNA and enhanced protein Tyr nitration. Liver-specific GS-deficient mice showed increased locomotion, impaired fear memory, and a slightly reduced life span. In conclusion, the present observations highlight the importance of hepatic GS for maintenance of ammonia homeostasis and establish the liver-specific GS KO mouse as a model with which to study effects of chronic hyperammonemia.hepatic encephalopathy | metabolic zonation | oxidative stress | RNA oxidation | glutamine

show abstract

Section: Discussionmentioning

confidence: 99%

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Qvartskhava

Lang

Görg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…With respect to the grades 3 and 4 would respond even more dramatically. It is probable that, in the case of initial SHE, the responder rate proven functional heterogeneity of the hepatocytes, 15,16,[31][32][33] evidence was presented showing that glutamate, aspartate, with regard to HE gradation will improve with further continuation or higher dose of OA treatment.…”

Section: Adverse Events and Adverse Drug Reactionsmentioning

confidence: 99%

“…14-was 0.25 g/kg body weight and that consumed with lunch was 0.5 g/ kg body weight. In this way, ingestion of an identical amount of 16,[20][21][22][28][29][30][31][32] It has been proposed that, whereas aspartate and protein before determination of the postprandial ammonia, the NCTcitric dicarboxylates under pathological condition in cirrhotic A times, and the mental state at 1:00 PM was guaranteed.…”

mentioning

confidence: 99%

“…[20][21][22][23] In contrast to hepatic ammonia removal by urea drugs (OA: 4 patients; placebo: 5 patients). Long-term administration and glutamine synthesis, [14][15][16][20][21][22][23]31,32 recent findings suggest of either clomethiazole (4 patients), a drug used for treatment of alcohol-withdrawal syndrome, or a tranquilizer (1 patient) was also fundamentally different regulatory mechanisms for GS 27,[37][38][39] continued.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: Results of a placebo-controlled, double-blind study

et al. 1997

View full text Add to dashboard Cite

prandial venous ammonia concentrations in the OAOne hundred twenty-six patients with cirrhosis, hytreated group showed improvements in comparison perammonemia (ú50 mmol/L), and chronic (persistent) with placebo. In addition, venous fasting blood ammonia hepatic encephalopathy (HE), which developed spontaconcentration (P õ .01), mental state gradation (P õ neously without the existence of known precipitating .001), and PSEI (P õ .01), which includes the mental state factors, were enrolled in a randomized, double-blind, gradation, NCT-A time, and postprandial venous ammoplacebo-controlled clinical trial of intravenously adminnia in this trial, improved to a much higher degree in Hepatic encephalopathy (HE) is one of the major complicapresented are based on the total study sample (intent-to-tions of cirrhosis. Five years after the diagnosis of cirrhosis, treat analysis), which included 63 patients in the placebo the probability of developing at least one episode of this spegroup and 63 patients in the OA group. Of the 126 pa-cific form of decompensated cirrhosis is in the range of 26%. 1 tients, 114 met all the criteria for inclusion and com-Once clinical decompensation has occurred, however, the pleted the trial and treatment as outlined in the protocol prognosis (16% 1 to 22% 2 probability of survival at 5 years) (treated-per-protocol analysis). During baseline, the pla-compared with a survival probability of 55% 2 to 70% 1 in circebo and treatment groups were homogeneous with re-rhotic patients without HE is very poor. 1,2 Therefore, prevengard to mental states, NCT-A performance time, fasting tion and effective treatment of HE may have important progvenous blood ammonia levels, and Child-Pugh criteria. nostic implications in cirrhotic patients. Although a slight improvement occurred in the placeboHyperammonemia 3,4 by a variety of postulated mechagroup, NCT-A performance times (P õ .001) and post-nisms 3-8 is felt to be one of the primary pathogenetic factors in the development of HE. 8 The majority of therapeutic measures currently in use are therefore directed at reducing blood Abbreviations: HE, hepatic encephalopathy; SHE, subclinical hepatic encephalopathy; ammonia levels, 9-13 mainly by diminishing enteric ammonia OA, L-ornithine-L-aspartate; GS, glutamine synthetase; NCT-A, number connection test A; PSEI, portal systemic encephalopathy index.production. Otherwise, it is known that liver and muscle play From the 1 Martin-Luther-University Halle-Wittenberg, Department of Internal Median important part within the ammonia detoxification system, cine, Halle;

show abstract

“…[35][36][37][38][39][40][41] In addition, glutamate dehydrogenase (GDH) and glutaminase (GL) bring ammonia into the urea cycle from certain amino acids. 32,[42][43][44][45] as schematically shown in Figure 1. Therefore, altered activities or expression levels of these enzymes may be involved in myeloma cases with hyperammonemia.…”

Section: Introductionmentioning

confidence: 99%

In vitro excess ammonia production in human myeloma cell lines

et al. 1998

View full text Add to dashboard Cite

It is well known that cases with multiple myeloma reveal various clinical manifestations such as pancytopenia, hyperproteinemia, renal dysfunction, bone lesions, hypercalcemia and immunodeficiency. Recently, a few more clinical features associated with myeloma, such as salivary type hyperamylasemia and elevated serum C-reactive protein (CRP) concentration, have been reported. The elevation of CRP is thought to be related to interleukin-6 (IL-6) production by myeloma cells, because of identification of IL-6 as an autocrine and/or paracrine growth factor for myeloma cells. More recently, there have been several reports of cases with myeloma associated with hyperammonemia. This hyperammonemia is not considered to be due to liver dysfunction, because in most of these cases tests revealed normal hepatic function, and some cases showed different patterns of serum amino acid distribution than that associated with hepatic failure. However, there have been no apparent observations of ammonia production by myeloma cells. In this study, we used six human myeloma cell lines including KMS-18, which was recently established from a myeloma case associated with hyperammonemia. These lines were treated with MRA (mycoplasma removal agent) to observe ammonia production in vitro. They produced and released significantly higher levels of ammonia into culture medium than non-myeloma hematological cell lines or the HepG2 human hepatic carcinoma cell line. Although attempts to analyze the relative expression levels of the enzymes related to ammonia biosynthesis using the reverse transcriptase-polymerase chain reaction assay failed to detect any differences between these myeloma lines and other cell lines, in vitro excess ammonia production by the myeloma cells was confirmed and the relevance to clinical manifestations is discussed.

show abstract

Changes in Distribution and Activity of Glutamine Synthetase in Carbon Tetrachloride–Induced Cirrhosis in the Rat: Potential Role in Hyperammonemia

Cited by 51 publications

References 31 publications

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: Results of a placebo-controlled, double-blind study

In vitro excess ammonia production in human myeloma cell lines

Contact Info

Product

Resources

About