Clearance of Injected Heparin from the Blood

Eiber, Harold B.; Danishefsky, I.

doi:10.1038/1801359a0

Cited by 13 publications

(4 citation statements)

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“…The existence of many of these reactions has been inferred from the presence of sulfate conjugates in urine and secretions and from the study of detoxication mechanisms (64). Among those which have been observed in vivo or in tissue preparations are the sul furylation of many kinds of phenols (11,65,66,67), including triiodothyro nine (68) and tyrosine derivatives (69,70); of arylamines (71); steroids (72,73); mucopolysaccharides (11,74,75), heparin (76), and charonin (77); cerebrosides (78); and bilirubin (79).…”

Section: Sulfokinasesmentioning

confidence: 99%

Metabolism of Sulfur Compounds (Sulfate Metabolism)

Gregory¹,

Robbins²

1960

Annu. Rev. Biochem.

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SO much work has been published on sulfur compounds in the fourteen years since the last review in this series [Lugg (1)] that we have not attempted to cover the whole field. This paper is regretfully restricted to the metabo lism of sulfate, and many other areas must be slighted in which valuable developments have appeared. However, a few outstanding reviews and general works dealing with particular sulfur compounds should be mentioned: methionine (2), glutathione (3), lipoic acid (4), biotin and other compounds (5), protein sulfhydryl groups (6, 7), and a collection of papers in memory of C. Fromageot, including his complete bibliography (8). General reviews on sulfur metabolism have been published by Bersin (9), Young & Maw (10), and Dziewiatkowski (11).Although many good whole animal studies have appeared on the in corporation and distribution of sulfate [Dziewiatkowski (12)] and on the conjugation of phenolic compounds with sulfate, we shall report mainly en zymological work. Recent knowledge of enzyme reactions involving sulfate has been reviewed by Lipmann (13). The activation of sulfate to form a "high -energy" intermediate is the first step in its assimilation. Two paths are then open: the sulfate may be reduced, or it may be transferred. in which case the reaction is catalyzed by sulfokinases and various esters are formed. And finally, there are hydrolytic enzymes, the sulfatases, which split almost all sulfate esters. SULFATE ACTIVATIONDeMeio and his co-workers were the first to study phenyl sulfate forma tion in a ho mogenate (14). They showed that in a liver homogenate oxygen and mitochondria were necessary for phenyl sulfate synthesis and that ATP would replace these requirements (15). These workers were also among the first to show that the sulfate activating and -transferring systems could be separated (16). Bernstein & McGilvery (17) studied the conjugation of m aminophcnol in liver homogenatcs. By studying the kinetics of this system, they deduced that an intermediate activated sulfate was formed and that at least two enzymes were involved (18). They also showed that a com pound accumulated that would rapidly transfer sulfate when ATP, sulfate, 1 The survey of the literature pertaining to this review was concluded in September 1959.2 The following abbreviations are used in this review: AMP for adenosine mono phosphate; APS for adenosine-5'-phosphosulfate; p-NP and p-NPS for p-nitrophenol and its sulfate, respectively; PAP for 3'-phosphoadenosine-5 '-phosphate; PAPS for 3'-phosphoadenosine-5'-phosphosuJfate; PP for pyrophosphate; TPN+ and TPNH for oxidized and reduced tripho5phopyridine nucle otide, respectively. 347Annu. Rev. Biochem. 1960.29:347-364. Downloaded from www.annualreviews.org Access provided by Western Michigan University on 02/02/15. For personal use only.Quick links to online content Further ANNUAL REVIEWS

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Section: Sulfokinasesmentioning

confidence: 99%

Metabolism of Sulfur Compounds (Sulfate Metabolism)

Gregory¹,

Robbins²

1960

Annu. Rev. Biochem.

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“…However, because oftheir heterogeneous composition and their chemical properties, pharmacokinetic studies are difficult. Various studies have tried to clarify metabolic pathways of heparin and other sulfated glucosaminoglycans, using 35S as a tracing agent (1)(2)(3). Apart from a role ofthe kidneys in heparin pharmacokinetics, evidence was found for an uptake by the reticuloendothelial system of the liver, although results gathered with this technique have to be interpreted cautiously because oflow specific activity and rapid desulfation of the tracer substance.…”

Section: Introductionmentioning

confidence: 99%

Hepatic uptake of a modified low molecular weight heparin in rats.

Stehle

Friedrich²,

Sinn³

et al. 1992

J. Clin. Invest.

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Fractionated and unfractionated heparins are widely used as antithrombotic agents. Because of their heterogeneous composition, it is difficult to study the pharmacokinetics of these drugs. We now report on a new method for labeling low molecular weight heparins with "31I by binding tyramine to the anhydromannose end of the molecules. We examined the pharmacokinetics of the compound by intravenous injection of '31I-tyramine-heparin into Wistar rats. About 18% of the activity was found in the liver, whereas 33% was detected in urine. Biological activity in terms of Factor Xa inhibition was measurable. Since evidence from cell culture experiments implies that reticuloendothelial cell system receptors might be involved in heparin metabolism, maleylated BSA, a substance known to block scavenger receptors, was injected before the radiolabeled heparin compound. The liver uptake was reduced from 17.4 to 4.8%. Injection of unfractionated heparin before tracer application caused a considerable increase in urine excretion of the tracer substance. To our knowledge, this is the first report that liver uptake of heparins is linked to scavenger receptor mediated mechanisms in vivo. This interaction of heparins with scavenger receptors might play an important role in the biology of the vessel wall. (J. Clin. Invest. 1992Invest. .90:2110Invest. -2116

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“…In this publi-has been complicated in the past by the lack of a simple, quick, and curate method of measuring the development of rubella antibodies* The generally Sever et al (2 ) have shown the usefulness * P a r t of this lvork was supported by uspHs…”

mentioning

confidence: 97%

“…Serological diagnosis of rubella infection of fresh cell sedimentation (cell packing) for concentrating viral complement fixing (CF) antigens demonstrated recently was used for the concentration of rubella C F antigen (1,2).…”

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confidence: 99%

Preparation and Characterization of Tritiated Heparin

Barlow¹,

Cardinal²

1966

Experimental Biology and Medicine

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The properties of heparin as an inhibitor of blood coagulation have been known for several years ( 1 ) . However, the physiology and metabolism of heparin has been only slightly clarified. With the preparation of radioactive heparin the possibility for quantitative metabolic studies of this substance can be undertaken. Eiber and Danishefsky ( 2 ) reported on the preparation of heparin labeled with S35 by biosynthesis in the dog. With this material they have studied the disposition of heparin after injection by following its disappearance from the circulation (3) and its deposition in various organs(4). More recently Levy and Petracek ( 5) have prepared heparin-Sa5 by the chemical reaction of pyridine S3503 or trimethylamine-S3503 with partially desulfated heparin. Both preparative methods led to biologically active preparations with radioactivity counts of the order of lo5 dpm/mg. There is still a need for a radioactive heparin labeled with another isotope, e.g., tritium, in positions other than the sulfate moiety which is the most labile bond in the molecule. Recent interest involves the use of graphite-benzalkonium-heparin ( GBH) surfaces in artificial organs especially the artificial heart valves (6) ; an understanding of the mechanism of action of this surface might be facilitated by a stable isotopically labeled heparin molecule.Tritiation. We used a modification of the Hempel Toepler pump set-up for catalytic tritiation. The apparatus will be described later. Three hundred mg of sodium heparin ( 157 p/mg) was suspended in 3 ml of water and 2 ml of diethyleneglycol monoethyl ether. One hundred milligrams of 30% palladium on carbon were then added. The resultant suspension was frozen in a liquid nitrogen bath, evacuated, and the vessel filled with hydrogen. The catalyst was saturated with hydrogen by mixing with a magnetic stirrer for one hour at atmospheric pressure and temperature. Five curies of tritium gas were pumped into the 10 ml reaction vessel after freezing and evacuation. The reaction mixture was then adjusted to roo,m temperature and atmospheric pressure with hydrogen. The reaction for the catalytic exchange tritiation was 48 hours with constant mixing. After 48 hours the catalyst was separated from the reaction mixture by filtration. Labile tritium was removed by distilling five 2501 ml portions of water from the product. The crude product weighed 275 mg and assayed 137 pCJmg by scintillation counting.Purification and characterization. The sample was purified by dissolving it in isotonic sodium chloride and precipitating with cetylpyridinium chloride (CPC), 3 mg per mg of heparin; the resultant complex was redissolved in 2 M sodium chlo'ride and the heparin precipitated with absolute alcohol, 2 volumes. The heparin was redissolved in 0.5 R/I sodium chloride and the entire purification procedure was repeated. The slightly colored product weighed 1.50 mg, had a specific radioactivity of 8.2 ,pC/mg and a biological potency in the USP assay of 124 p/mg.The radioactive powder diluted with cold startin...

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Clearance of Injected Heparin from the Blood

Cited by 13 publications

References 4 publications

Metabolism of Sulfur Compounds (Sulfate Metabolism)

Metabolism of Sulfur Compounds (Sulfate Metabolism)

Hepatic uptake of a modified low molecular weight heparin in rats.

Preparation and Characterization of Tritiated Heparin

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