Changes in serum and red blood cell membrane lipids in patients treated with interferon ribavirin for chronic hepatitis C

Tanaka, Hiroto; Miyano, Motoshige; Ueda, Hiroki; Fukui, Koji; Ichinose, Masakazu

doi:10.1007/s10238-005-0085-0

Cited by 17 publications

(13 citation statements)

References 19 publications

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“…In addition, we were able to demonstrate that supplementation with the antioxidant GSH prevents RBV-induced oxidative changes in vitro [43]. Another recent study also found RBV-induced changes in erythrocyte membrane lipids in patients treated with RBV/IFN, which were interpreted as oxidative damage [44].…”

Section: Mechanisms Of Ribavirin-induced Anemiasupporting

confidence: 57%

Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

Russmann

Grattagliano²,

Portincasa³

et al. 2006

CMC

125

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Ribavirin (RBV) is an antiviral nucleoside analogue commonly used in combination with interferon for the treatment of chronic hepatitis C. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and often RBV dose reduction, which may compromise sustained virologic response. Anemia is likely related to extensive RBV accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. RBV exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system. Concentration-dependent toxicity and improvement of anemia upon dose-reduction point towards the importance of pharmacokinetic factors for RBV-induced anemia. On the other hand, pronounced variability in the correlation between RBV concentration and Hb reduction limits the prediction of anemia based on plasma or erythrocyte concentrations in individual patients and points towards additional factors determining individual susceptibility to RBV-induced anemia. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia. Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Future research on RBV pharmacokinetics and pharmacodynamics, as well as erythrocyte antioxidant defense mechanisms may improve safety and efficacy of RBV therapy and guide the development of new treatments for RBV-induced anemia and alternative antiviral agents.

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Section: Mechanisms Of Ribavirin-induced Anemiasupporting

confidence: 57%

Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

Russmann

Grattagliano²,

Portincasa³

et al. 2006

CMC

125

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“…16) Since these cells have less deformability and are easily removed in RES, they are difficult to detect in circulating blood in vivo. Although echinocytes have not been reported in patients receiving ribavirin so far, a decrease in mean cell volume of erythrocyte and mean cell Hb was found during ribavirin treatment, 21) suggesting that morphological change in erythrocyte is induced by ribavirin treatment. The present in vitro study revealed for the first time that intracellular ribavirin accumulation induced echinocytic transformation.…”

Section: Resultsmentioning

confidence: 88%

Morphological Transformation and Phosphatidylserine Exposure in Erythrocytes Treated with Ribavirin

Homma

Hosono

Hasegawa³

et al. 2009

Biological & Pharmaceutical Bulletin

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Ribavirin (1-b -D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide), a synthetic guanosine analogue, is phosphorylated intracellularly to exert antiviral activities against DNA and RNA viruses.1,2) Combination therapy with interferon (IFN) for hepatitis C virus (HCV) infection revealed that higher rate of sustained virus response was achieved by adjuvant effects of ribavirin. [3][4][5] One of the major side effects of ribavirin is a reversible hemolytic anemia, which sometimes necessitates cessation of ribavirin co-administration. [6][7][8] Ribavirin-induced hemolytic anemia is likely due to excessive accumulation of phosphorylated ribavirin in erythrocytes.9-12) Once incorporated into erythrocytes via es-type nucleoside transporter, 13) ribavirin is subjected to intracellular phosphorylation and converted to its phosphorylated metabolites.14) Therefore the concentration of erythrocyte ribavirin including phosphorylated metabolites is 160-fold higher than that in plasma. 9,10) Recent studies have revealed that erythrocyte ribavirin induced intracellular ATP deficiency, leading to downregulation of the hexose monophosphate shunt resulting in accelerated oxidative damage on erythrocyte cell membrane.15) Significant alterations including band 3 aggregation were also found; these are known associated with erythrophagocytosis in reticuloendothelial system (RES).15) Intracellular ATP deficiency may cause ATP-dependent morphological transformation 16) and enzyme activity modification in erythrocytes. It is widely accepted that erythrocytes with ATP deficiency decrease in deformability, which is associated with erythrocyte removal in RES. ATP depletion is known to produce phosphatidylserine (PS) exposure on plasma membrane by inactivation of ATP-dependent aminophospholipid translocase activity.17) Since PS exposure is a key step for phagocytic removal in various cells including thalassemic erythrocytes, 18,19) its association with ribavirin-induced hemolytic anemia may arise.In the present study, we examined morphological transformation and PS exposure in ribavirin-treated erythrocytes invitro in association with intracellular ribavirin accumulation and ribavirin-induced hemolytic anemia. MATERIALS AND METHODS Materials and Reagent SolutionsRibavirin, dipyridamole, and 3-methoxycitidine methosulfate were purchased from Sigma-Aldrich (St. Louis, U.S.A.). Annexin V-fluorescein isothiocyanate conjugate (FITC) Kit was purchased from Immunotech, Beckman-Coulter (Miami, U.S.A.). All other reagents and solvents for assay were of analytical or reagent grade and were purchased from Wako Chemicals (Osaka, Japan) and Sigma-Aldrich.Ribavirin Treatment of Erythrocytes Whole blood was obtained into heparinized tubes from a healthy subject and was centrifuged at 1000ϫg. Erythrocytes were isolated by removing the supernatant, washed 4 times with 3 volumes of PBS and suspended in HEPES-buffered Tyrode solution (137 mM NaCl, 2.7 mM KCl, 12 mM HEPES, 1 mM MgCl 2 , 2 mM CaCl 2 , and 5.6 mM dextrose; pH 7.4) to make the 20% hematocrit preparat...

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“…Nevertheless, type I IFNs decrease membrane contents of saturated FAs and increase unsaturated FAs (92). In patients with chronic hepatitis C infection, treatment with IFNα2 reduces the deformability and membrane fluidity of red blood cells, which may result in hemolytic anemia, a frequent side effect of IFN therapy (96). Another downside of IFN-induced 25-HC expression is its capacity to inhibit SREBP1, which not only drives FAS but also stimulates transcription of interleukin-1, a secreted inflammatory protein with wide-ranging antibacterial functions (97).…”

Section: Modulation Of Lipid Synthesis By Viruses and Ifnsmentioning

confidence: 99%

Effects of Interferons and Viruses on Metabolism

2016

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Interferons (IFNs) are potent pleiotropic cytokines that broadly alter cellular functions in response to viral and other infections. These alterations include changes in protein synthesis, proliferation, membrane composition, and the nutritional microenvironment. Recent evidence suggests that antiviral responses are supported by an IFN-induced rewiring of the cellular metabolism. In this review, we discuss the roles of type I and type II IFNs in regulating the cellular metabolism and biosynthetic reactions. Furthermore, we give an overview of how viruses themselves affect these metabolic activities to promote their replication. In addition, we focus on the lipid as well as amino acid metabolisms, through which IFNs exert potent antiviral and immunomodulatory activities. Conversely, the expression of IFNs is controlled by the nutrient sensor mammalian target of rapamycin or by direct reprograming of lipid metabolic pathways. These findings establish a mutual relationship between IFN production and metabolic core processes.

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Changes in serum and red blood cell membrane lipids in patients treated with interferon ribavirin for chronic hepatitis C

Cited by 17 publications

References 19 publications

Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

Morphological Transformation and Phosphatidylserine Exposure in Erythrocytes Treated with Ribavirin

Effects of Interferons and Viruses on Metabolism

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