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Xiong XF, Chen DD, Zhu HJ, Ge WH. Prognostic value of endogenous and exogenous metabolites in liver transplantation. Biomark Med 2020; 14:1165-1181. [PMID: 32969246 DOI: 10.2217/bmm-2020-0073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation has been widely accepted as an effective intervention for end-stage liver diseases and early hepatocellular carcinomas. However, a variety of postoperative complications and adverse reactions have baffled medical staff and patients. Currently, transplantation monitoring relies primarily on nonspecific biochemical tests, whereas diagnosis of multiple complications depends on invasive pathological examination. Therefore, a noninvasive monitoring method with high selectivity and specificity is desperately needed. This review summarized the potential of endogenous small-molecule metabolites as biomarkers for assessing graft function, ischemia-reperfusion injury and liver rejection. Exogenous metabolites, mainly those immunosuppressive agents with high intra- and inter-individual variability, were also discussed for transplantation monitoring.
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Affiliation(s)
- Xiao-Fu Xiong
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China.,College of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Ding-Ding Chen
- College of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Huai-Jun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China.,Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Wei-Hong Ge
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China
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Attard JA, Dunn WB, Mergental H, Mirza DF, Afford SC, Perera MTPR. Systematic Review: Clinical Metabolomics to Forecast Outcomes in Liver Transplantation Surgery. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 23:463-476. [PMID: 31513460 DOI: 10.1089/omi.2019.0086] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Liver transplantation is an effective intervention for end-stage liver disease, fulminant hepatic failure, and early hepatocellular carcinoma. Yet, there is marked patient-to-patient variation in liver transplantation outcomes. This calls for novel diagnostics to enable rational deployment of donor livers. Metabolomics is a postgenomic high-throughput systems biology approach to diagnostic innovation in clinical medicine. We report here an original systematic review of the metabolomic studies that have identified putative biomarkers in the context of liver transplantation. Eighteen studies met the inclusion criteria that involved sampling of blood (n = 4), dialysate fluid (n = 4), bile (n = 5), and liver tissue (n = 5). Metabolites of amino acid and nitrogen metabolism, anaerobic glycolysis, lipid breakdown products, and bile acid metabolism were significantly different in transplanted livers with and without graft dysfunction. However, criteria for defining the graft dysfunction varied across studies. This systematic review demonstrates that metabolomics can be deployed in identification of metabolic indicators of graft dysfunction with a view to implicated molecular mechanisms. We conclude the article with a horizon scanning of metabolomics technology in liver transplantation and its future prospects and challenges in research and clinical practice.
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Affiliation(s)
- Joseph A Attard
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, United Kingdom.,Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Warwick B Dunn
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.,Phenome Centre Birmingham, University of Birmingham, Birmingham, United Kingdom.,School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Simon C Afford
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - M Thamara P R Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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Bonneau E, Tétreault N, Robitaille R, Boucher A, De Guire V. Metabolomics: Perspectives on potential biomarkers in organ transplantation and immunosuppressant toxicity. Clin Biochem 2016; 49:377-84. [DOI: 10.1016/j.clinbiochem.2016.01.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 12/23/2015] [Accepted: 01/07/2016] [Indexed: 12/27/2022]
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Lluch P, Segarra G, Medina P. Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis. World J Gastroenterol 2015; 21:9466-9475. [PMID: 26327755 PMCID: PMC4548108 DOI: 10.3748/wjg.v21.i32.9466] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 06/05/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.
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Ferrigno A, Di Pasqua LG, Berardo C, Richelmi P, Vairetti M. Liver plays a central role in asymmetric dimethylarginine-mediated organ injury. World J Gastroenterol 2015; 21:5131-5137. [PMID: 25954086 PMCID: PMC4419053 DOI: 10.3748/wjg.v21.i17.5131] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/24/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.
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Cure E, Cure MC, Tumkaya L, Kalkan Y, Aydin I, Kirbas A, Yilmaz A, Yuce S, Gokce MF. Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats. SAUDI JOURNAL OF GASTROENTEROLOGY : OFFICIAL JOURNAL OF THE SAUDI GASTROENTEROLOGY ASSOCIATION 2014. [PMID: 25253365 DOI: 10.4103/1319-3767.141690.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIM Ischemia/reperfusion (I/R) injury in the liver occurs after a prolonged period of ischemia followed by restoration of hepatic blood perfusion. During the surgery of abdominal aorta, I/R injury causes damage to lower extremities and many organs, especially liver. The antioxidant and tumor necrosis factor-alpha (TNF-α) suppression effects of topiramate (TPM) have been reported in several studies. We evaluated the potential protective effect of TPM on cellular damage in liver tissue during I/R injury. MATERIALS AND METHODS Thirty male Wistar albino rats were divided into three groups: Control, I/R, and I/R plus TPM (I/R + TPM) groups. Laparotomy without I/R injury was performed in the control group. After laparotomy, cross-ligation of infrarenal abdominal aorta was applied for 2 h in I/R groups that was followed by 2 h of reperfusion. TPM (100 mg/kg/day) was orally administrated to the animals in the I/R + TPM group for seven consecutive days before I/R procedure. RESULTS The I/R group's TNF-α and interleukin-6 (IL-6) levels were significantly higher than those of the control (P = 0.010; P = 0.002) and I/R + TPM groups (P = 0.010; P = 0.002, respectively). Asymmetric dimethyl arginine (ADMA) levels of I/R group were higher than the control (P = 0.015) and I/R + TPM groups. I/R caused serious histopathological damage to liver tissue; however, TPM led to very low histopathological changes. CONCLUSION Our data demonstrated that TPM treatment prominently decreases the severity of liver I/R injury. TPM pretreatment may have preventive effects on liver injury via I/R during intra-abdominal surgery.
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Affiliation(s)
- Erkan Cure
- Department of Internal Medicine, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
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Cure E, Cure MC, Tumkaya L, Kalkan Y, Aydin I, Kirbas A, Yilmaz A, Yuce S, Gokce MF. Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats. Saudi J Gastroenterol 2014; 20:297-303. [PMID: 25253365 PMCID: PMC4196345 DOI: 10.4103/1319-3767.141690] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 07/18/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIM Ischemia/reperfusion (I/R) injury in the liver occurs after a prolonged period of ischemia followed by restoration of hepatic blood perfusion. During the surgery of abdominal aorta, I/R injury causes damage to lower extremities and many organs, especially liver. The antioxidant and tumor necrosis factor-alpha (TNF-α) suppression effects of topiramate (TPM) have been reported in several studies. We evaluated the potential protective effect of TPM on cellular damage in liver tissue during I/R injury. MATERIALS AND METHODS Thirty male Wistar albino rats were divided into three groups: Control, I/R, and I/R plus TPM (I/R + TPM) groups. Laparotomy without I/R injury was performed in the control group. After laparotomy, cross-ligation of infrarenal abdominal aorta was applied for 2 h in I/R groups that was followed by 2 h of reperfusion. TPM (100 mg/kg/day) was orally administrated to the animals in the I/R + TPM group for seven consecutive days before I/R procedure. RESULTS The I/R group's TNF-α and interleukin-6 (IL-6) levels were significantly higher than those of the control (P = 0.010; P = 0.002) and I/R + TPM groups (P = 0.010; P = 0.002, respectively). Asymmetric dimethyl arginine (ADMA) levels of I/R group were higher than the control (P = 0.015) and I/R + TPM groups. I/R caused serious histopathological damage to liver tissue; however, TPM led to very low histopathological changes. CONCLUSION Our data demonstrated that TPM treatment prominently decreases the severity of liver I/R injury. TPM pretreatment may have preventive effects on liver injury via I/R during intra-abdominal surgery.
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Affiliation(s)
- Erkan Cure
- Department of Internal Medicine, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Medine C. Cure
- Department of Biochemistry, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Levent Tumkaya
- Department of Histology and Embryology, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Yildiray Kalkan
- Department of Histology and Embryology, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Ibrahim Aydin
- Department of Surgery, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Aynur Kirbas
- Department of Biochemistry, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Arif Yilmaz
- Department of Gastroenterology, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Suleyman Yuce
- Department of Internal Medicine, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
| | - Mehmet F. Gokce
- Department of Physiology, Recep Tayyip Erdogan University, School of Medicine, Rize, Turkey
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Changes in ADMA/DDAH pathway after hepatic ischemia/reperfusion injury in rats: the role of bile. BIOMED RESEARCH INTERNATIONAL 2014; 2014:627434. [PMID: 25243167 PMCID: PMC4160639 DOI: 10.1155/2014/627434] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/17/2014] [Accepted: 07/17/2014] [Indexed: 12/20/2022]
Abstract
We investigated the effects of hepatic ischemia/reperfusion (I/R) injury on asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor), protein methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH) (involved, resp., in ADMA synthesis and degradation), and the cationic transporter (CAT). Male Wistar rats were subjected to 30 or 60 min hepatic ischemia followed by 60 min reperfusion. ADMA levels in serum and bile were determined. Tissue ADMA, DDAH activity, DDAH-1 and CAT-2 protein, DDAH-1 and PRMT-1 mRNA expression, GSH/GSSG, ROS production, and lipid peroxidation were detected. ADMA was found in bile. I/R increased serum and bile ADMA levels while an intracellular decrease was detected after 60 min ischemia. Decreased DDAH activity, mRNA, and protein expression were observed at the end of reperfusion. No significant difference was observed in GSH/GSSG, ROS, lipid peroxidation, and CAT-2; a decrease in PRMT-1 mRNA expression was found after I/R. Liver is responsible for the biliary excretion of ADMA, as documented here for the first time, and I/R injury is associated with an oxidative stress-independent alteration in DDAH activity. These data are a step forward in the understanding of the pathways that regulate serum, tissue, and biliary levels of ADMA in which DDAH enzyme plays a crucial role.
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Age-related changes in ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion. Exp Gerontol 2013; 50:45-51. [PMID: 24269305 DOI: 10.1016/j.exger.2013.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 11/06/2013] [Accepted: 11/12/2013] [Indexed: 12/26/2022]
Abstract
BACKGROUND Liver function is affected during ischemia/reperfusion (IR). We evaluated the effect of the aging process on selected parameters determining the NO level in rat liver subjected to IR. METHODS The animals were divided into the C-2 and the IR-2 group of young rats (2-4 months old) and the C-12 and the IR-12 group of older rats (12-14 months old). Livers belonging to the IR-2 and the IR-12 group were subjected to partial ischemia (60 min) and reperfusion (4 h). Blood samples were obtained after surgeries to estimate the activity of aminotransferases, as well as just before ischemia and during reperfusion (15, 120, and 240 min) to estimate concentration of arginine (Arg) and its derivatives: asymmetric and symmetric dimethylarginine (ADMA, SDMA). After IR, dimethylarginine dimethylaminohydrolase (DDAH) activity and protein concentration of inducible nitric oxide synthase (iNOS) were measured in liver homogenates. RESULTS In the IR-2 group ADMA level increased the most between 15 and 120 min of reperfusion and was the highest of all the groups (0.72±0.2 μmol/l). In the IR-12 group ADMA level decreased significantly and was lower compared to all the other groups at 15 min (0.42±0.2 μmol/l) and to IR-2 at 120 (0.52±0.1 μmol/l) and 240 min (0.38±0.1 μmol/l) of reperfusion. Only the IR-2 group SDMA level increased significantly between 15 (0.75±0.9 μmol/l) and 240 min (1.0±1.2 μmol/l) of reperfusion. At the beginning of the surgery the Arg level was significantly higher in young rats (C-2: 102.1±35.7 μmol/l; IR-2: 114.63±28.9 μmol/l) than in older ones (C-12: 41.88±44.7 μmol/l; IR-12: 28.64±30.6 μmol/l). In the C-2 group the Arg level (77.41±37.5 μmol/l) and Arg/ADMA (A/A) ratio (138.03±62.8 μmol/l) were significantly higher compared to the ischemic groups at 15 min and to all the other groups at 120 (Arg: 47.17±31.7 μmol/l; A/A: 88.28±66.2 μmol/l) and 240 min (Arg: 43.87±21.9 μmol/l; A/A: 118.02±106.3 μmol/l). In the IR-2 group Arg level (11.4±12.0 μmol/l) and A/A ratio (16.11±16.2 μmol/l) decreased significantly at 15 min and during the next phase of reperfusion the levels of those parameters were low, comparably to those in IR-12. As a result of IR, a decrease in DDAH activity and an increase in iNOS protein concentration were observed only in the young rats. CONCLUSIONS We found that in the non-ischemic groups the Arg level may be affected by the aging process. Under IR conditions, important changes in DDAH-ADMA-NO pathway were observed only in young livers.
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Influence of ezetimibe on ADMA-DDAH-NO pathway in rat liver subjected to partial ischemia followed by global reperfusion. Pharmacol Rep 2013; 65:122-33. [PMID: 23563030 DOI: 10.1016/s1734-1140(13)70970-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Revised: 10/02/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND We evaluated effect of ezetimibe on selected parameters determining NO level in rat liver subjected to ischemia reperfusion (IR). METHODS Rats received ezetimibe (5 mg/kg) (groups E0 and EIR) or saline solution (groups C0 and CIR) intragastrically for 21 days. Then, the livers of CIR and EIR underwent ischemia (60 min) and reperfusion (4 h). Blood samples were obtained before surgery to estimate activities of aminotransferases, and just before ischemia and during reperfusion to estimate asymmetric and symmetric dimethylarginine (ADMA, SDMA) and arginine (Arg) levels. After IR, dimethylarginine dimethylaminohydrolase (DDAH) activity and endothelial nitric oxide synthase (eNOS) protein concentration were measured in liver homogenates. DDAH and protein arginine methyltransferase (PRMT) mRNA were quantified by real-time PCR in liver tissue samples. RESULTS In CIR, the ADMA level was significantly higher compared to all other groups in 30 min and to E0 group in 120 min of reperfusion. In EIR, ADMA was low, compared to non-ischemic groups. At 30 and 120 min of reperfusion, in non-ischemic groups the level of Arg and Arg/ADMA ratio were significantly higher than in ischemic groups and E0 was the group with the highest levels of those parameters of all. In CIR, eNOS protein concentration was significantly lower than in ezetimibe-treated groups. Activity of DDAH was significantly higher in E0 than in non-treated groups. In ischemic groups, DDAH mRNA expression was significantly higher than in non-ischemic ones and PRMT mRNA expression was significantly higher in C0 than in all other groups. CONCLUSIONS Influence of ezetimibe on ADMA/DDAH/NO pathway demonstrated in this work may suggest protective properties of this drug on rat livers injured by IR and, to a lower extent, on livers non-subjected to IR.
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Kasumov T, Edmison JM, Dasarathy S, Bennett C, Lopez R, Kalhan SC. Plasma levels of asymmetric dimethylarginine in patients with biopsy-proven nonalcoholic fatty liver disease. Metabolism 2011; 60:776-81. [PMID: 20869086 PMCID: PMC3012158 DOI: 10.1016/j.metabol.2010.07.027] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 07/15/2010] [Accepted: 07/16/2010] [Indexed: 01/12/2023]
Abstract
Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are produced by breakdown of proteins that have been methylated posttranslationally at an arginine residue. Plasma levels of ADMA are elevated in insulin resistance states. Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and varying degrees of hepatic dysfunction. Because ADMA is metabolized in the liver, we hypothesized that ADMA levels will be high in patients with NAFLD as a consequence of hepatic dysfunction and insulin resistance. Plasma levels of ADMA, SDMA, total homocysteine, glucose, and insulin were measured in nondiabetic patients with biopsy-proven NAFLD (11 steatosis and 24 nonalcoholic steatohepatitis) and 25 healthy subjects. Plasma ADMA levels were significantly higher (P = .029) in patients with biopsy-proven NAFLD (0.43 ± 0.21 μmol/L) compared with controls (0.34 ± 0.10 μmol/L). However, when adjusted for insulin resistance (homeostasis model assessment), the difference between 2 groups was not evident. Plasma SDMA levels were similar in all 3 groups. Plasma levels of ADMA were positively correlated with plasma total homocysteine levels (P = .003). Plasma levels of SDMA were negatively correlated with estimated glomerular filtration rate (P = .016) and positively correlated with plasma total homocysteine levels (P = .003). The ratio of ADMA/SDMA was positively correlated with body mass index (P = .027). Elevated plasma concentrations of ADMA in biopsy-proven NAFLD were primarily related to insulin resistance. Hepatic dysfunction in NAFLD does not appear to make significant contribution to changes in plasma methylarginine levels.
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Affiliation(s)
- Takhar Kasumov
- Department of Gastroenterology, Cleveland Clinic, Cleveland, OH 44195, USA
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Trocha M, Merwid-Ląd A, Szuba A, Chlebda E, Pieśsniewska M, Sozański T, Szeląg A. Effect of simvastatin on nitric oxide synthases (eNOS, iNOS) and arginine and its derivatives (ADMA, SDMA) in ischemia/reperfusion injury in rat liver. Pharmacol Rep 2010; 62:343-51. [DOI: 10.1016/s1734-1140(10)70274-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Revised: 10/06/2009] [Indexed: 11/30/2022]
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Richir MC, Bouwman RH, Teerlink T, Siroen MPC, de Vries TPGM, van Leeuwen PAM. The prominent role of the liver in the elimination of asymmetric dimethylarginine (ADMA) and the consequences of impaired hepatic function. JPEN J Parenter Enteral Nutr 2009; 32:613-21. [PMID: 18974239 DOI: 10.1177/0148607108321702] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), the enzyme which converts the amino acid arginine into nitric oxide (NO). ADMA has been identified as an important risk factor for cardiovascular diseases. Besides the role of ADMA in cardiovascular diseases, it also seems to be an important determinant in the development of critical illness, (multiple) organ failure, and the hepatorenal syndrome. ADMA is eliminated from the body by urinary excretion, but it is mainly metabolized by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes that convert ADMA into citrulline and dimethylamine. DDAH is highly expressed in the liver, which makes the liver a key organ in the regulation of the plasma ADMA concentration. The prominent role of the liver in the elimination of ADMA and the consequences of impaired hepatic function on ADMA levels will be discussed in this article.
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Affiliation(s)
- Milan C Richir
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
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Becker T, Mevius I, de Vries DK, Schaapherder AFM, zu Vilsendorf AM, Klempnauer J, Frölich JC, Tsikas D. The L-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications. Nitric Oxide 2008; 20:61-7. [PMID: 18948222 DOI: 10.1016/j.niox.2008.10.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2008] [Revised: 08/08/2008] [Accepted: 10/03/2008] [Indexed: 12/21/2022]
Abstract
The L-arginine/nitric oxide (L-Arg/NO) pathway is altered in liver and kidney diseases. However, the status of the L-Arg/NO pathway during and after orthotopic transplantation is insufficiently investigated and findings are uncertain because of analytical shortcomings. Also, most human studies have focused on individual members of the L-Arg/NO pathway such as nitrate or asymmetric dimethylarginine (ADMA). In the present article we report on a pilot study investigating extensively the status of the L-Arg/NO pathway before and during orthotopic liver transplantation (OLT). By using fully validated, highly sensitive and specific GC-MS and GC-MS/MS methods nitrite, nitrate, ADMA and its hydrolysis product dimethylamine (DMA), L-arginine and L-ornithine were measured in blood and urine. Our study gives strong evidence of the exceptional importance of hepatic dimethylarginine dimethylaminohydrolase (DDAH) activity for the elimination of systemic ADMA. In end-stage liver disease the synthesis of NO and ADMA as well as the DDAH activity are elevated. However, increase in DDAH activity is insufficient to efficiently eliminate overproduced ADMA. The transplanted liver graft is capable of clearing ADMA in a rapid and sufficient manner. In contrast to studies from other groups, our study shows that in OLT as well as in living donor kidney transplantation, the second study reported here, reperfusion of the graft does not cause drastic alterations to the L-Arg/NO pathway with regard to NO synthesis. In the OLT study the concentration of circulating L-arginine fell temporally dramatically, while L-ornithine levels increased diametrically, most likely due to elevation of arginase activity. However, the relatively long-lasting decrease in plasmatic L-arginine in OLT seems not to have affected NO synthesis after reperfusion. Our OLT study suggests that liver reperfusion is associated with greatly elevated activity of proteolytic and hydrolytic enzymes including DDAH and arginase. Suppression of proteolytic and hydrolytic activity in transplantation could be a useful measure to improve outcome and remains to be investigated in further studies on larger patient collectives. The importance of analytical chemistry in this area of research is also discussed in this article.
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Affiliation(s)
- Thomas Becker
- Department of Visceral and Transplant Surgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
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Wilcken DEL, Sim AS, Wang J, Wang XL. Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of L-arginine on its metabolism. Mol Genet Metab 2007; 91:309-17; discussion 308. [PMID: 17560156 DOI: 10.1016/j.ymgme.2007.04.017] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2007] [Revised: 04/30/2007] [Accepted: 04/30/2007] [Indexed: 12/12/2022]
Abstract
Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase (NOS), has been identified as a new and emerging contributor to, or marker for, cardiovascular risk. The ADMA-mediated regulation of nitric oxide (NO) production is determined by the quantitative bioavailability of intracellular and extracellular ADMA. Dimethylarginine dimethylaminohydrolase (DDAH), which is ubiquitously expressed in tissues, especially liver and kidney, converts the majority of the ADMA to citrulline. In this review, we discuss a new regulatory mechanism for the metabolism of ADMA in which L-arginine acts as a competitive inhibitor of DDAH activity. This novel regulatory pathway is consistent with ADMA contributing to cardiovascular risk when levels are increased but not when levels are within the normal range. The pathway then has a physiological role in the regulation of NO production by preventing overproduction of NO. The regulatory role of L-arginine on ADMA may explain the unexpected outcomes in some L-arginine supplementation studies. This paper also reviews associations between the metabolism of ADMA and insulin resistance, smoking and homocysteine which are all associated with an increased risk of vascular disease.
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Affiliation(s)
- David E L Wilcken
- Department of Cardiovascular Medicine, The University of New South Wales and the Prince of Wales Hospital, Sydney, Australia.
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Perioperative kinetics of the nitric oxide derivatives nitrite/nitrate during orthotopic liver transplantation. Nitric Oxide 2007; 16:177-80. [DOI: 10.1016/j.niox.2006.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2006] [Revised: 06/20/2006] [Accepted: 07/06/2006] [Indexed: 11/21/2022]
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Siroen MPC, Teerlink T, Nijveldt RJ, Prins HA, Richir MC, van Leeuwen PAM. The Clinical Significance of Asymmetric Dimethylarginine. Annu Rev Nutr 2006; 26:203-28. [PMID: 16848705 DOI: 10.1146/annurev.nutr.26.061505.111320] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.
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Affiliation(s)
- Michiel P C Siroen
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.
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18
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Abstract
This review provides a summary of the applications and potential applications of metabolite profiling (i.e. metabolomics) in monitoring organ transplants. While the concept of metabolomics is relatively new to organ transplantation, the idea of measuring metabolites as a quick, noninvasive probe of organ function is not. Indeed, metabolite measurements of serum creatinine have long been used to assess pre- and post-operative organ function. Over the past 10 years, a number of lesser-known, organ-specific metabolites have also been shown to be good diagnostic indicators of both organ function and viability. In general, metabolomics offers a complementary picture to what can be revealed via techniques based on genomics, proteomics or histology. Because metabolic changes typically happen within seconds or minutes after an 'event', whereas some transcript, protein abundance or tissue changes may take place over days or weeks, metabolomic measurements may offer a particularly useful and inexpensive diagnostic tool to monitor donor organ viability or to detect organ rejection. The excitement associated with metabolomics, however, must be tempered by the fact that the technology for rapid metabolite identification is still in its infancy, and that metabolites are but one part of a very complex picture pertaining to organ function.
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Affiliation(s)
- D S Wishart
- Department of Computing Science, University of Alberta, Edmonton, AB, Canada.
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Abstract
Asymmetric dimethylarginine (ADMA) has been recognized as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. Its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is highly expressed in the liver. Considering the liver as a crucial organ in the clearing of ADMA, we hypothesized increased ADMA levels during hepatic failure and, consequently, a decline of ADMA concentrations after successful liver transplantation. The aim of the present study was to investigate the role of the liver in the metabolism of ADMA in patients undergoing liver transplantation. In this prospective study, we investigated the course of ADMA concentrations in 42 patients undergoing liver transplantation and results showed that preoperative ADMA concentrations were higher in patients with acute (1.26 micromol/L, P < .001) and in patients with chronic (.69 micromol/L, P < .001) hepatic failure compared with healthy volunteers (.41 micromol/L). In addition, ADMA concentrations decreased from the preoperative day to the first postoperative day in both the acute (Delta(ADMA): -.63 micromol/L, P = .005) and the chronic hepatic failure group (Delta(ADMA): -0.15 micromol/L, P < .001). Furthermore, in patients who experienced acute rejection, ADMA concentrations were higher during the whole first postoperative month compared with nonrejectors (P = .012). Moreover, in 11 of 13 rejectors (85%) a clear increase in ADMA concentration preceded the onset of the first episode of rejection, which was confirmed by liver biopsy. In conclusion, our results indicate that the transplanted liver graft is quickly capable of clearing ADMA, suggesting preservation of DDAH. In addition, increased ADMA concentrations in the posttransplantation period reflect serious dysfunction of the liver graft during acute rejection.
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Tsikas D, Rode I, Becker T, Nashan B, Klempnauer J, Frölich JC. Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2alpha in end-stage liver disease. Hepatology 2003; 38:1063-4. [PMID: 14512899 DOI: 10.1053/jhep.2003.50455] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
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Tsikas D, Rode I, Becker T, Nashan B, Klempnauer J, Frölich JC. Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2alpha in end-stage liver disease. Hepatology 2003. [PMID: 14512899 DOI: 10.1002/hep.1840380440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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