The urea cycle and related pathways in the liver of Walker-256 tumor-bearing rats

Pereira, Sandra Regina Corbello; Darronqui, Elaine; Constantin, Jorgete; Silva, Mário da Rocha Alves da Henrique; Yamamoto, Nair Seiko; Bracht, Adelar

doi:10.1016/j.bbadis.2003.12.001

Cited by 25 publications

(41 citation statements)

References 16 publications

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“…This is an unexpected finding because it has been observed that in both arthritic and tumour-bearing rats, ureagenesis from alanine and other substrates is considerably diminished and that this diminution correlates with the diminution of gluconeogenesis (Yassuda-Filho et al 2003;Corbello-Pereira et al 2004). However, it must stressed that a diminution of glucose production from alanine without a corresponding change in urea plus ammonia production represents an apparent unbalance between the carbon and nitrogen fluxes.…”

Section: Discussionmentioning

confidence: 93%

“…This alteration is diminution of gluconeogenesis from alanine, which has been reported to occur in rats with sepsis (Filkins & Cornell 1974;Spitzer et al 1985), adjuvant-induced arthritis (Fedatto-Jr et al 1999;Yassuda-Filho et al 2003) and rats bearing malignant tumours such as the Walker-256 tumour (Williams & Siddiqui 1990;Corbello-Pereira et al 2004) and mammary adenocarcinoma (Liu et al 1990). Each factor alone, TNFa and IL1b, was able to induce inhibition of gluconeogenesis.…”

Section: Discussionmentioning

confidence: 93%

“…This observation, although corroborating the more elevated hepatic gluconeogenesis in some cancer models, is difficult to reconcile with the decreased gluconeogenesis in animals with sepsis and adjuvant-induced arthritis which also present elevated levels of TNFa (Filkins & Cornell 1974;Spitzer et al 1985;Fedatto-Jr et al 1999). Also it does not explain the reduced hepatic gluconeogenesis from alanine in rats bearing the Walker-256 tumour (Liu et al 1990;Williams & Siddiqui 1990;Corbello-Pereira et al 2004). Furthermore, a study in mice revealed a significant diminution of the expression of the gluconeogenic key-enzyme phosphoenolpyruvate carboxykinase by TNFa, an observation which suggests decreased gluconeogenesis (Hill & McCallum 1992).…”

mentioning

confidence: 98%

“…There are several reports about stimulation of hepatic gluconeogenesis in tumour-bearing animals (Shearer et al 1983(Shearer et al & 1984Blumberg et al 1993;Fischer et al 1997) and in cancer patients (Agteresh et al 2000;Leij-Halfwerk et al 2000). However, there are also reports about diminution of hepatic gluconeogenesis in the tumour-bearing state, especially when alanine is the gluconeogenic precursor (Liu et al 1990;Williams & Siddiqui 1990;Corbello-Pereira et al 2004).…”

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confidence: 99%

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Low Doses of Tumour Necrosis Factor α and Interleukin 1β Diminish Hepatic Gluconeogenesis from Alanine in vivo

Kelmer-Bracht

Broetto-Biazon

Sá‐Nakanishi

et al. 2006

Basic Clin Pharma Tox

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Previous reports have attributed a stimulating action on hepatic gluconeogenesis to tumour necrosis factor a (TNFa) administered to rats at high doses (250 mg/kg). However, in adjuvant-induced arthritic rats, which present TNFa and other interleukins in the circulation, hepatic gluconeogenesis is diminished. The same occurs in some types of experimental cancer models as, for example, rats bearing the Walker-256 tumour. The present work represents an attempt of reproducing in rats gluconeogenesis inhibition by interleukins using low instead of high doses of both TNFa and interleukin 1b (IL1b). TNFa and IL1b at doses of up to 10 mg/kg were given endovenously to rats and, after six hours, gluconeogenesis from alanine and several related parameters were evaluated in the isolated haemoglobin-free perfused rat liver. Livers from rats injected with TNFa and IL1b, either alone or in combination, presented diminished gluconeogenesis. The degrees of inhibition caused by TNFaπIL1b, TNFa and IL1b were, respectively, 48.5, 38.8 and 30.4%. TNFa also diminished oxygen uptake. No action on urea and ammonia production was found. Possibly, both TNFa and IL1b contribute to the decreased rates of hepatic gluconeogenesis that were found in rats with arthritis, sepsis and some kinds of cancer, but not to the decreased rates of ureagenesis.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Low Doses of Tumour Necrosis Factor α and Interleukin 1β Diminish Hepatic Gluconeogenesis from Alanine in vivo

Kelmer-Bracht

Broetto-Biazon

Sá‐Nakanishi

et al. 2006

Basic Clin Pharma Tox

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“…3 Gluconeogenesis and ureogenesis from alanine, on the other hand, are also lower in livers from tumour-bearing rats. 4,5 Furthermore, the presence of the Walker-256 tumour does not affect hepatic gluconeogenesis from substrates such as lactate and pyruvate when the latter are infused in the presence of high and non-physiological ammonia concentrations (0.5 mM). 5 These results are in clear contrast with results obtained with animals bearing several other types of tumours in which stimulation of hepatic gluconeogenesis was found.…”

Section: Introductionmentioning

confidence: 99%

Metabolic fluxes in the liver of rats bearing the Walker‐256 tumour: influence of the circulating levels of substrates and fatty acids

Veiga

Silva

Teodoro

et al. 2007

Cell Biochemistry & Function

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Studies on fatty acid and amino acid metabolism in the liver of Walker-256 tumour-bearing rats have revealed several changes. Comparisons, however, have been based on experiments performed with non-physiological, frequently unrealistic, substrate concentrations. The aim of the present work was to examine the influence of physiological substrate concentrations on gluconeogenesis, ketogenesis and related parameters. Isolated livers were perfused and substrates were infused at concentrations that were reported to occur in healthy and tumour-bearing rats. Ketogenesis and the mitochondrial NADH/NAD+ ratio were smaller in the tumour-bearing condition at low (0.2 mM) and high (0.8 mM) oleate concentrations. In the absence of oleate, gluconeogenesis from alanine (0.7 mM) and gluconeogenesis plus the associated changes in oxygen uptake due to lactate/pyruvate (2/0.2 and 6/0.3 mM) were smaller in livers of tumour-bearing rats. However, the response of gluconeogenesis from lactate/pyruvate in livers of tumour-bearing rats to 0.8 mM oleate was more pronounced so that a trend towards normalization was apparent at high substrate and oleate concentrations. Gluconeogenesis from 0.7 mM alanine was not significantly changed by oleate in the tumour-bearing state; in the control condition, stimulation occurred at 0.2 mM oleate and inhibition at 0.8 mM oleate. This diminution almost equalized the hepatic alanine-dependent gluconeogenesis of both control and tumour-bearing rats. Ureogenesis was smaller in the tumour-bearing state and was not affected by oleate. It was concluded that the high concentrations of fatty acids and lactate/pyruvate, which predominate in rats bearing the Walker-256 tumour, could be effective in normalizing the gluconeogenic response of livers from tumour-bearing rats.

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Production of cachexia mediators by Walker 256 cells from ascitic tumors

Rebeca

Bracht

Noleto

et al. 2008

Cell Biochemistry & Function

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In neoplasic cachexia, chemical mediators seem to act as initiators or perpetuators of this process. Walker 256 cells, whose metabolic properties have so far been little studied with respect to cancer cachexia, are used as a model for the study of this syndrome. The main objective of this research was to pinpoint the substances secreted by these cells that may contribute to the progression of the cachectic state. Since inflammatory mediators seem to be involved in the manifestation of this syndrome, the in vitro production of nitric oxide (NO), cytokines (tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6)), and prostaglandin E2 (PGE2) was evaluated in Walker 256 cells isolated from ascitic tumors. After 4 or 5 h, a significant increase in NO production was observed (2.55 +/- 1.56 and 4.05 +/- 1.99 nmol NO per 10(7) cells, respectively). When isolated from a 6-day-old tumor, a significantly lower production of IL-6 and higher production of TNF-alpha than in cells from a 4-day-old tumor were observed, indicating a relationship between the production of cytokines and the time of tumor development after implantation. Considerable production of PGE(2) by Walker 256 cells isolated from the 6-day-old tumor was also observed. Polyamines were also determined in Walker 256 cells. Levels of putrescine, spermidine, and spermine did not show significant differences in tumors developed during 4 or 6 days. Direct evidence of the release of proinflammatory cytokines and PGE2 by Walker 256 cells suggests that these mediators can drive the cachectic syndrome in the host, the effect being dependent on tumor development time.

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The urea cycle and related pathways in the liver of Walker-256 tumor-bearing rats

Cited by 25 publications

References 16 publications

Low Doses of Tumour Necrosis Factor α and Interleukin 1β Diminish Hepatic Gluconeogenesis from Alanine in vivo

Low Doses of Tumour Necrosis Factor α and Interleukin 1β Diminish Hepatic Gluconeogenesis from Alanine in vivo

Metabolic fluxes in the liver of rats bearing the Walker‐256 tumour: influence of the circulating levels of substrates and fatty acids

Production of cachexia mediators by Walker 256 cells from ascitic tumors

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