Expression of haptoglobin receptors in human hepatoma cells

Okuda, Masahiro; Tokunaga, Rikio; Taketani, Shigeru

doi:10.1016/0167-4889(92)90249-b

Cited by 24 publications

(17 citation statements)

References 22 publications

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“…As a soluble acute phase serum protein, the primary function of Hp is to bind hemoglobin and facilitate its clearance from the circulation by binding to haptoglobin receptors on liver cells (7,8). The binding affinity of Hp to the hepatocyte receptor increases for the Hp-Hb complex.…”

Section: Discussionmentioning

confidence: 99%

“…As expected, nonlytic HDL lacking Hpr did not compete for Hpr binding. Competition binding experiments with Hp were unreliable due to its tendency to aggregate at high concentrations (data not shown) (8). However, Hp binding was measured at lower concentrations (Fig.…”

Section: Tlf-1 Binding To T B Brucei-thementioning

confidence: 99%

“…The Hp-Hb complex has been shown to bind with high affinity to mammalian cells. Human hepatocytes, in culture, expressed about 84,000 Hp receptors per cell, with a dissociation constant (K d ) of 7.4 nM (8). The internalized Hp-Hb complex is targeted to the lysosome where it is degraded; however the heme moiety is preserved.…”

mentioning

confidence: 99%

“…Haptoglobin avidly binds hemoglobin (Hb) released into the bloodstream and facilitates the rapid clearance of Hb from the circulatory system by the liver (7,8). The Hp-Hb complex has been shown to bind with high affinity to mammalian cells.…”

mentioning

confidence: 99%

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Haptoglobin-related Protein Mediates Trypanosome Lytic Factor Binding to Trypanosomes

Drain

Bishop

Hajduk

2001

Journal of Biological Chemistry

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Trypanosome lytic factor (TLF-1) is an unusual high density lipoprotein (HDL) found in human serum that is toxic to Trypanosoma brucei brucei and may be critical in preventing human infections by this parasite. TLF-1 is composed of four major apolipoproteins: apolipoprotein AI, apolipoprotein AII, paraoxonase, and the primate-specific haptoglobin-related protein (Hpr). Hpr is greater than 90% homologous to haptoglobin (

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Section: Discussionmentioning

confidence: 99%

Section: Tlf-1 Binding To T B Brucei-thementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Haptoglobin-related Protein Mediates Trypanosome Lytic Factor Binding to Trypanosomes

Drain

Bishop

Hajduk

2001

Journal of Biological Chemistry

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“…2 Hp-Hb binds to the aminoterminal part of a scavenger receptor cysteine-rich domain region of CD163 and the cytoplasmic tail of the receptor conveys cellular uptake of the Hp-Hb complex by receptor-mediated endocytosis. 2 Earlier studies have also reported uptake of Hp-Hb by a receptordependent mechanism in hepatocytes, 8,68 but the crucial role of the macrophages in Hp-Hp uptake is indicated by the Hp-Hb accumulation in plasma of patients with depletion of the macrophage population because of treatment with the biologic drug gemtuzumab ozogamicin that targets CD33-positive myeloblastic cells. 69 In contrast to the Ca 2ϩ -dependent high-affinity CD163 binding elicited by Hp-Hb complex formation, 2 Hp alone does not bind the receptor.…”

Section: Haptoglobin: a Hemoglobin Scavenger Facilitating The Anti-inmentioning

confidence: 99%

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Nielsen

Moestrup

2009

Blood

135

107

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Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme. Because of the high resemblance between haptoglobin and haptoglobinrelated protein, the receptor also takes up the complex of hemoglobin and the HDL- IntroductionHaptoglobin (Hp), an abundant acute phase plasma glycoprotein of the ␣ 2 -globulin fraction, was initially reported in 1938 by Polonovski and Jayle to be a "plasma substance" that binds hemoglobin (Hb). 1 In agreement with this initial characterization and its designation as "haptoglobin" (Greek: haptein, "to bind" ϩ [hemo]globin), Hp has a well-established role in binding of "free" Hb released into the circulation during the process of intravascular hemolysis. By capturing the liberated Hb, Hp protects against toxic effects associated with Hb, and it facilitates Hb clearance through endocytosis by the macrophage scavenger receptor CD163. 2 Later studies of human and primate plasma revealed variant forms of Hp as well as the existence of an Hp-related protein (Hpr) that recently has been shown also to bind Hb. As highlighted in this review, novel functions of Hp depend on high-affinity interactions with Hb and lipoprotein and subsequent receptor recognition of the resulting complexes. Toxicity of hemoglobin released during intracellular hemolysisIntravascular hemolysis, which accounts for approximately 10% to 20% of total red blood cell destruction, 3 changes Hb from being an intracellular O 2 /CO 2 transporter to a highly toxic substance in plasma. This toxicity arises from the heme iron, which can react with endogenous hydrogen peroxide to produce free radicals, which in turn may cause severe oxidative tissue damage, 4 particularly in the kidney. 5 In addition to the oxidative toxicity of Hb, Hb is a potent scavenger of nitric oxide (NO), a signaling molecule that functions as a critical regulator of smooth muscle relaxation, endothelial adhesion molecule expression, and platelet activation and aggregation. 6,7 The reaction of Hb with NO is fast and irreversible, leading to the production of nitrate and methemoglobin. If allowed to occur, this Hbmediated consumption of vascular NO, referred to as NOscavenging, thus limits the bioavailabili...

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Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity

Levy

Adamson²,

Phillips

et al. 2006

Hepatology

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Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate ( C hronic hepatitis C virus (HCV) infection is a major public health problem affecting over 4 million people in the United States and more than 170 million individuals worldwide. 1,2 In addition, chronic HCV is a causative factor for approximately 50% of the cases of hepatocellular carcinoma in the United States, and is the single most common indication for orthotopic liver transplantation worldwide. 3,4 However, treatment of HCV infection remains problematic. The current standard of care is a combination of interferon alpha (IFN-␣) and ribavirin. This combination treatment is limited by severe side effects that often lead to premature cessation of therapy. 5 The major toxicity associated with ribavirin is a dose-dependent hemolytic anemia, which occurs in approximately 50% of treated individuals, resulting in a ribavirin dose reduction. 6 The development of anemia usually starts after 4 weeks of therapy and can be precipitous.Coupling of ribavirin to a carrier molecule offers the potential of a therapeutic with improved safety and efficacy by targeting drug delivery of ribavirin to key tissues infected by HCV while preventing the hemolytic anemia that is caused by exposure of red blood cells to free ribavirin. Targeting of drugs by attachment to carrier molecules for delivery to specific tissues via receptor-mediated endocytosis is a recently established method for improv-

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Expression of haptoglobin receptors in human hepatoma cells

Cited by 24 publications

References 22 publications

Haptoglobin-related Protein Mediates Trypanosome Lytic Factor Binding to Trypanosomes

Haptoglobin-related Protein Mediates Trypanosome Lytic Factor Binding to Trypanosomes

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity

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