Effect of rosiglitazone on asymmetric dimethylarginine metabolism in thioacetamide-induced acute liver injury

Bekpınar, Seldağ; Vardagli, Duygu; Ünlüçerçi, Yeşim; Can, Ayten; Uysal, Müjdat; Gürdöl, Figen

doi:10.1016/j.pathophys.2015.06.003

Cited by 10 publications

(13 citation statements)

References 35 publications

(35 reference statements)

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“…Recently, Mookerjee (Mookerjee et al 2015) reported a decreased expression of DDAH-1 isoform in the liver of cirrhotic patients. Moreover, in TAA-induced ALF in rodents, an increase in plasma ADMA level was shown to correlate with the reduced activity of DDAH in the liver (Bekpinar et al 2015; Develi-Is et al 2013) and brain tissue (Milewski et al 2015). An increased ADMA content in plasma and brain tissue have also been reported in rat models of chronic cirrhosis (Balasubramaniyan et al 2012; Laleman et al 2005; Mookerjee et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

2016

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Alterations in brain nitric oxide (NO)/cGMP synthesis contribute to the pathogenesis of hepatic encephalopathy (HE). An increased asymmetrically dimethylated derivative of l-arginine (ADMA), an endogenous inhibitor of NO synthases, was observed in plasma of HE patients and animal models. It is not clear whether changes in brain ADMA reflect its increased local synthesis therefore affecting NO/cGMP pathway, or are a consequence of its increased peripheral blood content. We measured extracellular concentration of ADMA and symmetrically dimethylated isoform (SDMA) in the prefrontal cortex of control and thioacetamide (TAA)-induced HE rats. A contribution of locally synthesized dimethylarginines (DMAs) in their extracellular level in the brain was studied after direct infusion of the inhibitor of DMAs synthesizing enzymes (PRMTs), S-adenosylhomocysteine (AdoHcy, 2 mM), or the methyl donor, S-adenosylmethionine (AdoMet, 2 mM), via a microdialysis probe. Next, we analyzed whether locally synthesized ADMA attains physiological significance by determination of extracellular cGMP. The expression of PRMT-1 was also examined. Concentration of ADMA and SDMA, detected by positive mode electrospray LC–DMS–MS/MS, was greatly enhanced in TAA rats and was decreased (by 30 %) after AdoHcy and AdoMet infusion. TAA-induced increase (by 40 %) in cGMP was unaffected after AdoHcy administration. The expression of PRMT-1 in TAA rat brain was unaltered. The results suggest that (i) the TAA-induced increase in extracellular DMAs may result from their effective synthesis in the brain, and (ii) the excess of extracellular ADMA does not translate into changes in the extracellular cGMP concentration and implicate a minor role in brain NO/cGMP pathway control.

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Section: Introductionmentioning

confidence: 99%

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

2016

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“…Thus, 2‐aminoadipate has been proposed as a potential small‐molecule marker of oxidative stress . Likewise, there is evidence that circulating asymmetric dimethylarginine levels increase in conditions of oxidative stress . Asymmetric dimethylarginine is a product of methylation of arginine residues in proteins by the action of protein‐arginine methyltransferases .…”

Section: Discussionmentioning

confidence: 99%

“…As such, inactivation of DDAH because of irinotecan‐induced oxidative stress may lead to the accumulation of asymmetric dimethylarginine in the liver, which would be subsequently released into circulation (Figure C). In fact, elevation of circulating asymmetric dimethylarginine has been observed in various pathological conditions associated with liver dysfunction . Circulating levels of cystathionine may be augmented as an autocorrective response to oxidative stress .…”

Section: Discussionmentioning

confidence: 99%

“…43 Likewise, there is evidence that circulating asymmetric dimethylarginine levels increase in conditions of oxidative stress. 44,45 Asymmetric dimethylarginine is a product of methylation of arginine residues in proteins by the action of protein-arginine methyltransferases. 46 Because more than 90% of asymmetric dimethylarginine generated is metabolized by dimethylargine dimethylaminohydrolase (DDAH), 47 hepatic DDAH activity is an important determinant of circulating asymmetric dimethylarginine levels.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients

Bao

Kim

et al. 2018

The Journal of Clinical Pharma

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The purpose of this study was to identify early circulating metabolite changes implicated in the mechanism of action of irinotecan, a DNA topoisomerase I inhibitor, in cancer patients. A liquid chromatography-tandem mass spectrometry-based targeted metabolomic platform capable of measuring 254 endogenous metabolites was applied to profile circulating metabolites in plasma samples collected pre- and post-irinotecan treatment from 13 cancer patients. To gain further mechanistic insights, metabolic profiling was also performed for the culture medium of human primary hepatocytes (HepatoCells) and 2 cancer cell lines on exposure to SN-38 (an active metabolite of irinotecan). Intracellular reactive oxygen species (ROS) was detected by dihydroethidium assay. Irinotecan induced a global metabolic change in patient plasma, as represented by elevations of circulating purine/pyrimidine nucleobases, acylcarnitines, and specific amino acid metabolites. The plasma metabolic signature was well replicated in HepatoCells medium on SN-38 exposure, whereas in cancer cell medium SN-38 induced accumulation of pyrimidine/purine nucleosides and nucleobases while having no impact on acylcarnitines and amino acid metabolites. SN-38 induced ROS in HepatoCells, but not in cancer cells. Distinct metabolite signatures of SN-38 exposure in HepatoCells medium and cancer cell medium revealed different mechanisms of drug action on hepatocytes and cancer cells. Elevations in circulating purine/pyrimidine nucleobases may stem from nucleotide degradation following irinotecan-induced DNA double-strand breaks. Accumulations of circulating acylcarnitines and specific amino acid metabolites may reflect, at least in part, irinotecan-induced mitochondrial dysfunction and oxidative stress in the liver. The plasma metabolic signature of irinotecan exposure provides early insights into irinotecan mechanism of action in patients.

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“…Studies on the thioacetamide (TAA)-induced rat model of ALF revealed ADMA elevation in the plasma and both in the brain cortex tissue and extracellular space with parallel lowering of liver DDAH activity [37, 38, 50]. In addition, in the BDL rat model, ADMA level significantly raises in the peripheral blood, whereas the concentration of l -arginine decreases [51].…”

Section: Adma In Liver Dysfunction: Implications To the Hementioning

confidence: 99%

Asymmetric Dimethylarginine and Hepatic Encephalopathy: Cause, Effect or Association?

Czarnecka

Milewski

2016

Neurochem Res

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The methylated derivative of l-arginine, asymmetric dimethylarginine (ADMA) is synthesized in different mammalian tissues including the brain. ADMA acts as an endogenous, nonselective, competitive inhibitor of all three isoforms of nitric oxide synthase (NOS) and may limit l-arginine supply from the plasma to the enzyme via reducing its transport by cationic amino acid transporters. Hepatic encephalopathy (HE) is a relatively frequently diagnosed complex neuropsychiatric syndrome associated with acute or chronic liver failure, characterized by symptoms linked with impaired brain function leading to neurological disabilities. The l-arginine—nitric oxide (NO) pathway is crucially involved in the pathomechanism of HE via modulating important cerebral processes that are thought to contribute to the major HE symptoms. Specifically, activation of this pathway in acute HE leads to an increase in NO production and free radical formation, thus, contributing to astrocytic swelling and cerebral edema. Moreover, the NO-cGMP pathway seems to be involved in cerebral blood flow (CBF) regulation, altered in HE. For this reason, depressed NO-cGMP signaling accompanying chronic HE and ensuing cGMP deficit contributes to the cognitive and motor failure. However, it should be remembered that ADMA, a relatively little known element limiting NO synthesis in HE, may also influence the NO-cGMP pathway regulation. In this review, we will discuss the contribution of ADMA to the regulation of the NO-cGMP pathway in the brain, correlation of ADMA level with CBF and cognitive alterations observed during HE progression in patients and/or animal models of HE.

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Effect of rosiglitazone on asymmetric dimethylarginine metabolism in thioacetamide-induced acute liver injury

Cited by 10 publications

References 35 publications

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

Intracerebral Administration of S-Adenosylhomocysteine or S-Adenosylmethionine Attenuates the Increases in the Cortical Extracellular Levels of Dimethylarginines Without Affecting cGMP Level in Rats with Acute Liver Failure

Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients

Asymmetric Dimethylarginine and Hepatic Encephalopathy: Cause, Effect or Association?

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