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PubMedDate not supplied

Arginase as a useful factor for the diagnosis of colorectal cancer liver metastases.

The present work is a continuation of studies on arginase as a marker in the diagnosis of colorectal cancer liver metastases (CRCLM). The purpose of the study was the evaluation of the arginase test in comparison with other colorectal cancer tests such as CEA, CA 19-9 and biochemical markers of liver function such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The studies were conducted on blood serum from 85 patients with CRCLM obtained one to two days before tumor resection. The control group comprised 140 healthy blood donors and 81 patients with various non-malignant gastrointestinal diseases. Raised arginase activity was observed in serum of 85% of CRCLM patients, whereas elevated levels of CEA and CA 19-9 were found in 63% and 42% of patients, respectively. The combination of CEA or CA 19-9 with the arginase assay improved their sensitivity, but the sensitivity of the combined parameters was not higher than that of the arginase test itself. AST and ALT activities were increased in about 30% of CRCLM patients. The specificity of the arginase test calculated for 221 control subjects was 76%. It can thus be concluded that the determination of serum arginase activity can be helpful in the diagnosis of patients with colorectal cancer liver metastases.

Adult↗

PubMed2006

Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma.

BACKGROUND: Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC) nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production--due to competition with neuronal NO-synthase (nNOS) for the common substrate, L-arginine. Furthermore, in a guinea pig model of allergic asthma, airway arginase activity is markedly increased after the early asthmatic reaction (EAR), leading to deficiency of agonist-induced, epithelium-derived NO and subsequent airway hyperreactivity. In this study, we investigated whether increased arginase activity after the EAR affects iNANC nerve-derived NO production and airway smooth muscle relaxation. METHODS: Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5-16 Hz)-induced relaxation was measured in tracheal open-ring preparations precontracted to 30% with histamine in the presence of 1 microM atropine and 3 microM indomethacin. The contribution of NO to EFS-induced relaxation was assessed by the nonselective NOS inhibitor Nomega-nitro-L-arginine (L-NNA, 100 microM), while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor Nomega-hydroxy-nor-L-arginine (nor-NOHA, 10 microM). Furthermore, the role of substrate availability to nNOS was measured in the presence of exogenous L-arginine (5.0 mM). RESULTS: At 6 h after ovalbumin-challenge (after the EAR), EFS-induced relaxation (ranging from 3.2 +/- 1.1% at 0.5 Hz to 58.5 +/- 2.2% at 16 Hz) was significantly decreased compared to unchallenged controls (7.1 +/- 0.8% to 75.8 +/- 0.7%; P < 0.05 all). In contrast to unchallenged controls, the NOS inhibitor L-NNA did not affect EFS-induced relaxation after allergen challenge, indicating that NO deficiency underlies the impaired relaxation. Remarkably, the specific arginase inhibitor nor-NOHA normalized the impaired relaxation to unchallenged control (P < 0.05 all), which effect was inhibited by L-NNA (P < 0.01 all). Moreover, the effect of nor-NOHA was mimicked by exogenous L-arginine. CONCLUSION: The results clearly demonstrate that increased arginase activity after the allergen-induced EAR contributes to a deficiency of iNANC nerve-derived NO and decreased airway smooth muscle relaxation, presumably via increased substrate competition with nNOS.

Animals↗

PubMed2005

The therapeutic potential of drugs targeting the arginase pathway in asthma.

Arginine metabolism by arginases may be of importance in health and disease, either by competing with nitric oxide synthases for the common substrate or by the production of L-ornithine. L-ornithine serves as a precursor for L-proline and polyamines, which may be involved in tissue remodelling by promoting collagen synthesis and cell proliferation. Arginase activity potentiates airway reactivity by reducing the production of bronchodilatory nitric oxide. Increased arginase activity has been implicated in the development of allergen-induced airway hyper-responsiveness in experimental asthma. In addition, reduced L-arginine availability to inducible nitric oxide synthase by arginase may lead to an increased production of peroxynitrite, contributing to increased airway smooth muscle contractility, airway inflammation and cell damage in this disease. Recent studies demonstrate that the upregulation of arginase by T helper type 2 cytokines in lung tissue as well as in cultured airway fibroblasts indicates a possible role of the enzyme in airway re-modelling. These findings, in conjunction with human studies showing a role for arginase in acute asthma, open a new horizon for the therapeutic potential of drugs targeting the arginase pathway in asthma.

Animals↗

PubMedDate not supplied

Effects of folic acid and methotrexate on arginase activity in regenerating rat liver tissue.

Arginase (L-arginine-ureidohydrolase, EC 3.5.3.1) catalyses the hydrolysis of arginine to ornithine and urea. Its primary metabolic role is to remove the excess of ammonia through synthesis of urea. Ornithine, as a product of arginase reaction can be used for synthesis of polyamines. Rapid tissue growth after partial hepatectomy is accompanied by an increase in biosynthesis of polyamines. The aim of this study was to examine the importance of arginase in regenerating liver after partial hepatectomy and to investigate the influence of folic acid and methotrexate on arginase activity on this model of compensatory growth. It was established that arginase activity was significantly reduced in regenerating rat liver tissue at different time intervals after partial hepatectomy. Administration of folic acid to hepatectomized rats led to inhibition of arginase activity. Administration of methotrexate after hepatectomy increased the arginase activity.

Animals↗

PubMed2001

Possible implications of arginase and diamine oxidase in prostatic carcinoma.

Polyamine metabolism in prostatic tissue, which may give rise to prostatic hyperplasia by inducing cell proliferation, is controlled primarily by two enzymes: arginase and diamine oxidase (DAO). Arginase catalyzes the synthesis of ornithine, the precursor for polyamines from arginine, whereas DAO catalyzes the oxidation of diamines. such as spermine and spermidine, to a much less active compound called putrescine. In this study, we evaluated arginase and DAO activities in prostate tissues of 50 patients with benign prostatic hyperplasia and in 23 patients with prostatic carcinoma. Both DAO and arginase activities were found to be elevated in cancer tissues as compared to benign prostatic hyperplasia (fivefold and twofold, respectively; P < .001). A strong inverse correlation between arginase and DAO activities was observed in those in the cancer group (r = -0.65; P < .001). Gleason grades of prostatic carcinomas were well correlated with both arginase and DAO activities. Results suggest that DAO and arginase might play an essential role in the mechanism of prostatic disease process by modulating polyamine levels.

Aged↗

PubMed2001

Arginase levels are increased in patients with rheumatoid arthritis.

Arginase and nitric oxide synthase (NOS) compete for the same substrate, L-arginine. The reciprocal regulation of arginase and NOS in L-arginine-metabolizing pathways has recently been demonstrated. Since NOS is involved in the inflammation of human arthritides, we hypothesized that this reciprocal regulation might also occur within the inflamed synovium. The present study shows that both serum arginase activity and protein levels were significantly higher in patients with rheumatoid arthritis (RA) than in patients with systemic lupus erythematosus (SLE) or osteoarthritis (OA) or in healthy controls. Arginase protein concentrations in supernatants of monocyte cultures from RA patients were also significantly higher than in those from SLE or OA patients or healthy controls. In RA patients, there was a significant correlation between the serum concentrations of arginase protein and rheumatoid factor (r = 0.82, p < 0.0001). These data indicate that increased arginase production is seen in RA patients, but not in other immune-related diseases, suggesting that increased arginase production is unique to, and may play an important role in, the pathogenesis of RA disease.

Arginase↗

PubMed2001

[Changes in pancreatic arginase activity in pubertal and adult rats induced by castration].

Arginase activity in kidney, and small intestine in several mammalian species is sensitive to castration, a finding that could suggest their dependence on testosterone. However, as far as we know, information on regulation of pancreatic arginase activity is scarce. In this paper, the effect of orchidectomy on pancreatic arginase activity in pubescent and adult rats was studied. Male pubescent and adult rats, 21 days old and 4 months old, respectively, were orquidectomizades and sacrificed at various times post-surgery. Groups of intact rats served as controls. Arginase activity and proteins were measured in pancreatic tissue. The activity of this enzyme was measured in serum in addition to glucose, triglycerides and total proteins. In pubescent rats pancreatic and serum arginase activities peaked at day 5 post-surgery, increased arginase activity in adult rats was seen at day 20. Changes in serum and pancreatic proteins in pubescent, but not in adult, castrated rats were observed. Taken together, these results suggest that pancreatic arginase activity is androgen-dependent and that there is age-difference, probably due lo distinct patterns of hormone secretion in pubescent and adult rats.

Age Factors↗

PubMed1991

Physico-chemical properties of hepatocyte plasma-membrane-bound arginase.

Rat liver plasma-membrane-bound arginase was investigated in order to obtain data regarding its physico-chemical properties. Arginase bound to plasma membrane presented a specific activity of 0.74 +/- 0.09 IU/mg for the fully-activated enzyme, the pH of maximum activity being 9.8. Maximum stability was recorded at two pH values, 7 and 10.5 respectively. Mn2+ activated the enzyme, while Cu2+ and Zn2+, and to a lesser extend Co2+, showed a strong inhibitory effect. Ca2+ and Mg2+ had no effect at the concentrations assayed. The influence of temperature was studied in the presence and in the absence of Mn2+. The enzyme was stable up to 65 degrees C in both cases. Membrane- bound arginase showed an activation energy of 11.5 +/- 1.4 Kcal/mol between 20 and 40 degrees C, and 13.3 +/- 2.5 Kcal/mol between 40 and 60 degrees C. The Q10 for the same temperature ranges were 1.78 and 1.9 respectively. The membrane-bound enzyme presented two different Michaelis constants, one with high affinity (2.05 +/- 0.73 mM) and the other with low affinity for arginine (130 +/- 27.2 mM). Solubilized arginase showed very similar values. Among all the structural analogous assayed, only L-canavanine proved to be substrate for arginase, with and L-arginine/L-canavanine hydrolysis ratio of 5.8 +/- 0.28. No reactivity was found between plasma-membrane-bound arginase and anti-rat liver arginase antibodies raised in rabbits.

Animals↗

PubMed1985

Occurrence of cytotoxic autoantibody in rabbits by immunization with heterologous liver arginase: a possible implication in the mechanism of the autoimmune liver diseases.

Rat liver arginase was isolated from extracts of liver in a pure form. Monospecific antisera raised against the arginase reacted with arginase of liver but not with arginase of kidney, spleen, heart, lung, testis and brain. The antisera were, however, reactive with liver arginase of a variety of animals, including human, mouse, sheep, horse and cow as well as rabbit, a homologous animal used for immunization. The rabbit autoantibodies showed direct cytotoxic activity as well as antibody-dependent cell-mediated cytotoxicity to homologous rabbit hepatocytes. Immunocytochemical electron microscopic examination showed that the arginase was localized on the surfaces of rat hepatocytes and on intracellular organelles. These results suggest that liver arginase could be an important antigen of the liver with implications for the pathogenesis of autoimmune liver diseases.

Animals↗

PubMedDate not supplied

[Arginase activity in various tissues of rats in alcohol intoxication].

Effects of acute and chronic alcohol intoxication on activities of arginase, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (AcDH) were studied in rat liver, brain and kidney tissues. Alcohol intoxication altered both ureotelic (liver) and non-ureothelic (brain, kidney) arginase activity. The arginase activity in all the tissues studied was increased in chronic alcohol intoxication. Elevation in the arginase activity in liver tissue indicates that the urea cycle is activated as well as that hyperproduction of glutamic acid in brain may occur. Specific inhibitory effects of ethanol and acetaldehyde might be responsible for alterations of the arginase activity in all the tissues studied in acute alcohol intoxication. In vitro acetaldehyde at 5 X 10(-6) M concentration inhibited the arginase activity in partially purified preparations of brain and kidney tissues by 40-50% and of liver tissue--by 10-15%; 10% ethanol inhibited the liver enzyme by 90% and affected only slightly the activity of brain arginase.

Alcohol Dehydrogenase↗

PubMed1983

Elevated manganese concentration and arginase activity in livers of streptozotocin-induced diabetic rats.

The regulation of hepatic arginase (EC 3.5.3.1) activity was studied in diabetic rats fed ad libitum. Arginase activity in liver cytosol increased 2 to 3 days after injection of streptozotocin into rats and remained elevated (maximally 1.7-fold) 13 days postinjection. Radioimmunoassays indicated, however, that the amounts of immunoreactive arginase protein in livers of control and diabetic rats were similar. The specific activity of purified preparations of arginase from diabetic rats was approximately 1.5-fold higher than that from control rats. Manganese, a cofactor for arginase, was elevated by 4 days post-streptozotocin injection and remained elevated (maximally 1.6-fold) for at least 13 days. Most of the manganese in control and diabetic liver cytosols was associated with macromolecules and eluted with arginase activity upon gel filtration. These data establish that the enhanced arginase activity observed in diabetes is coincident with elevated cofactor concentration but not with elevated enzyme protein concentration.

Animals↗

PubMed1977

[Subcellular distribution of arginase and gamma-guanidino-butyrate-ureohydrolase in brain sections, neurons and glia].

Distribution of arginase and gamma-guanidine-butyrate-ureohydrolase in seven brain sections is studied. Specific activity of arginase in brain sections is 0.063-0.117 and of gamma-guanidine-butyrate-ureohydrolase -- 0.042-0.050 mcmoles of urea per 1 mg of protein for 30 min. Cortex and cerebellum neurons have the same arginase activity (0.12 mcmole/mg). Specific arginase activity in glial cerebellum cells is 3 times as much as in cortex glial cells (0.20 and 0.07 mcmole/mg respectively). The activity of gamma-guanidine-butyrate-ureohydrolase in glial cell is higher than in neurons. Subcellular distribution of both enzymes is studied in those brain sections where their activity is maximal. In cerebellum both enzymes were tested, in cortex -- gamma-guanidine-butyrate-ureohydrolase, in thalamus -- arginase. The highest specific arginase activity is found in cytoplasmic, microsomic and synaptosomic fractions. Gamma-Guanidine-butyrate-ureohydrolase is concentrated in cytoplasmic and synaptosomic fractions. Possible correlation of gamma-aminobutyric acid metabolism and participation of brain arginase in regulation of protein biosynthesis are discussed.

Animals↗

PubMed1996

Evidence for increased anionic arginase activity in pig enterocytes during development.

We have recently reported that the flux of L-arginine through arginase in enterocytes is increased in weaned pigs when compared with suckling animals (Blachier et al. 1993, Eur. J. Biochem. 216, 109-117). The aim of the present study was to characterize arginase activities at both stages of development. Enterocytes isolated from suckling animals were found to possess an anionic (50%) and a non-anionic (50%) form of arginase as judged from activities recovered from DEAE-cellulose ion exchange chromatography. In enterocytes isolated from weaned animals, anionic arginase was the major form representing 89% of arginase activity. This isoform is characterized by increased affinity for L-arginine (2 fold) and increased maximal velocity (39 fold) when compared with the anionic form originating from suckling piglet enterocytes. In conclusion, our data demonstrate that pig enterocytes are equipped with at least 2 isoforms of arginase and that anionic form of arginase activity appeared to be mainly responsible for the capacity of weaned pig enterocytes to catabolize L-arginine.

Animals↗

PubMed2003

Prenatal diagnosis for arginase deficiency: a case study.

Arginase deficiency is a rare, autosomal recessive, disorder of the urea cycle characterized by mild hyperammonaemia, hyperargininaemia, dibasic aminoaciduria and orotic aciduria, associated with progressive spastic tetraplegia, seizures, psychomotor retardation, and growth failure. We report a family who presented with their daughter at 4 years 11 months of age with an acute encephalopathy. Initial laboratory results revealed hyperammonaemia (160 micromol/L; normal 0-34), hyperargininaemia (512 micromol/L; normal 23-86) and orotic aciduria. A diagnosis of arginase deficiency was confirmed by enzyme assay, and treatment with a modified protein-restricted diet along with sodium benzoate therapy was initiated. Over time, intellectual development has been normal, but the child developed spasticity in her lower extremities. Subsequently, the mother presented at 6 weeks of pregnancy seeking prenatal diagnosis. Prenatal testing for arginase deficiency has only been reported in one other case. Arginase is not expressed in cultured amniotic fluid cells or chorionic villus samples. Testing for arginase activity assay in red blood cells, isolated by cordocentesis, was performed and predicted an unaffected fetus. The result was confirmed by postnatal enzyme analysis of red cells from the newborn. On the basis of our experience, prenatal diagnosis of arginase deficiency by cord red blood cell arginase activity assay appears possible.

Adult↗

PubMed2004

Modulation of intrinsic cavernous tone and nitric oxide production by arginase in rabbit corpus cavernosum.

PURPOSE: Arginase shares the common substrate L-arginine with nitric oxide synthase (NOS). We investigated the roles of NOS and arginase for modulating intrinsic and vasoconstrictor tone in rabbit corpus cavernosum (RCC). MATERIALS AND METHODS: Isolated RCC tissues were used for isometric tension experiments, and NOS and arginase activities. The endothelium lining RCC lacunar spaces was disrupted and/or removed by saponin treatment. RESULTS: Following stretch of approximately 1gm NG-nitro-L-arginine methyl ester (L-NAME) as a NOS inhibitor caused endothelium dependent contraction, while the potent and specific arginase inhibitor N omega-hydroxy-nor-L-arginine (nor-NOHA) caused endothelium dependent relaxation. Relaxation with nor-NOHA was reversed by L-NAME. In the presence of 10 mM L-arginine 0.1 mM nor-NOHA was ineffective. Pretreatment with 0.1 mM L-NAME and 0.1 mM nor-NOHA did not significantly affect the vasoconstrictor response to phenylephrine. The magnitude of contraction with 0.1 mM L-NAME and relaxation with 0.1 mM nor-NOHA during contraction induced by phenylephrine were not significantly different from changes with L-NAME and nor-NOHA under intrinsic basal tone. In the enzymatic study NOS and arginase were detectable in cavernous homogenates. Nor-NOHA inhibited arginase but not NOS activity. CONCLUSIONS: Results indicate that basal nitric oxide production from the endothelium regulates intrinsic cavernous tone and endogenous arginase activity in the endothelium modulates tone by inhibiting nitric oxide production, presumably through competition with constitutive NOS for the common substrate L-arginine.

Animals↗

PubMed2000

Expression of nitric oxide synthase isoforms and arginase in normal human skin and chronic venous leg ulcers.

Chronic venous ulcers, an example of abnormal wound healing, show chronic inflammation with defective matrix deposition which together with the underlying vascular pathology, result in delayed healing. L-arginine is known to be metabolized by one of two pathways: nitric oxide synthase (NOS), producing nitric oxide (NO), or arginase, producing ornithine. NO is involved in many pathological conditions including vascular and inflammatory disorders. This study therefore investigated the distribution, level and activity of NOS and arginase in chronic venous ulcers in comparison with normal skin, using immunocytochemistry, western blotting, and enzyme assays. The results demonstrated an increased distribution of both NOS and arginase in chronic venous ulcer tissue compared with normal skin, with inflammatory cells and vascular endothelial cells as the main sources. These data were confirmed by western blot analysis, which showed increased levels of both enzymes in chronic venous ulcers. Moreover, there was significantly increased activity of both total NOS (p<0.04) and inducible NOS (p<0.05) in chronic venous ulcer tissue compared with normal skin, and significantly increased activity of arginase (p<0.01) in chronic venous ulcer tissue in comparison with normal skin. NO is known to combine with hydroxyl free radicals forming peroxynitrite, a potent free radical which causes tissue destruction. NO overexpression in chronic venous ulcers may be involved directly or indirectly (through production of peroxynitrite) in the pathogenesis and delayed healing of chronic venous ulcers, through its effects on vasculature, inflammation, and collagen deposition. Arginase is known to enhance matrix deposition. Thus, increased levels of arginase in chronic venous ulcers could contribute to the pathogenesis of lipodermatosclerosis associated with chronic venous insufficiency, predisposing to the formation of chronic venous ulcers and also to matrix cuff formation around blood vessels.

Arginase↗

PubMed1992

Clinical significance of arginase in colorectal cancer.

Arginase, a potent immune inhibitor, existed in much greater abundance in the cytoplasm of cancer cells than in normal cells. Serum arginase levels from 31 patients with colorectal adenocarcinoma were determined by using enzyme immunoassay (mean +/- standard error = 18.96 +/- 4.83 ng/ml) and showed to be significantly higher than levels from control subjects (n = 115, 3.09 +/- 0.22 ng/ml) (P less than 0.005). Surgical samples of 15 patients were individually homogenized and assayed by the same method and revealed that the arginase level in tissues with colorectal cancer was two times greater than the level found in normal mucosal tissues (1.74 +/- 0.31 micrograms/g tissue versus 0.77 +/- 0.09 micrograms/g tissue, P less than 0.005). However, the serum arginase levels in patients with colorectal cancer were independent of their carcinoembryonic antigen (CEA) levels (n = 27, arginase 11.81 +/- 1.88 ng/ml, CEA 17.31 +/- 4.24 ng/ml, r = 0.084, P = 0.666). The results suggested that serum arginase level can be a valuable criterion for preoperative evaluation and possibly postoperative follow-up study. It can also combine with CEA determination to intensify the clinical assessment for colorectal cancer.

Adenocarcinoma↗

PubMed2004

Arginase induction promotes Trypanosoma cruzi intracellular replication in Cruzipain-treated J774 cells through the activation of multiple signaling pathways.

Given that arginase activation may effectively influence nitric oxide (NO) production in macrophages, we have investigated the intracellular signals that regulate L-arginine metabolism and its influence on Trypanosoma cruzi growth. We demonstrate that cruzipain (Cz), a parasite antigen, induces arginase I expression in J774 cells, and the pretreatment of Cz-treated cells with N-omega-hydroxy-L-arginine (arginase inhibitor) leads to a dramatic decrease in amastigote growth. The study of intracellular signals shows that genistein [tyrosine kinase (TK) inhibitor], KT5720 [protein kinase (PK) A inhibitor] and SB203580 [p38 mitogen-activated protein kinase (MAPK) inhibitor] significantly decrease Cz-induced arginase activation. However, calphostin C (PKC inhibitor) and PD98059 [p44/p42 MAPK kinase (MEK) inhibitor] did not cause a significant change. To determine if signaling pathways triggered by Cz were involved in the T. cruzi growth, we studied the effect of those inhibitors. In Cz-treated cells--pre-incubated with TK, PKA or p38 MAPK inhibitors--the balance of NO/urea was biased towards NO, and the amastigote growth was diminished. Besides, genistein and mainly KT5720 induced down-regulation of arginase I expression in Cz-treated cells. Thus, activation of TK, PKA and p38 MAPK by Cz induces an increase of arginase activity in macrophages and the subsequent T. cruzi growth.

Animals↗