Journal article
Resistance of heparinase-derived heparin fragments to biotransformation
The Journal of biological chemistry, Vol.264(3), pp.1570-1577
01/25/1989
DOI: 10.1016/S0021-9258(18)94225-0
PMID: 2912974
Abstract
The biotransformation of heparinase-derived heparin fragments was examined via a combined approach using 35S-labeled heparin fragments as well as unlabeled chemically defined heparin fragments. Rats dosed with either [35S]di-, tetra-, hexa-, or octasaccharide fragments (2 mg/kg body weight, intravenously) excreted 63-69% of the injected radioactivity into the urine within 24 h with two-thirds being excreted during the first 6 h. Gel permeation chromatography of the urinary material shows that the tetra- and octasaccharides have undergone minor (approximately 5%) depolymerization whereas no change was observed for the di- and hexasaccharides. No N-desulfation was demonstrated for any of the substances. The hexa- and octasaccharide metabolites present in the urine 24 h after dosing exhibited the same antifactor Xa activity as that of the injected material. A chemically defined trisulfated disaccharide and a hexasulfated tetrasaccharide were prepared and dosed in a similar manner. Only one metabolite was recovered from animals dosed with disaccharide. This compound was characterized by anion exchange chromatography, proton nuclear magnetic resonance spectroscopy, Fourier transform infrared spectrometry, and mass spectrometry and shown to be identical to the injected disaccharide. Five metabolites were isolated from the urine of rats dosed with the hexasulfated tetrasaccharide. The major metabolite, consisting of at least 65% of the total, was characterized as described for the disaccharide and shown to be identical to the injected compound. The remaining material appeared to be disaccharides and, possibly, a tetrasaccharide conjugate. Taken together, our results show that the heparinase-derived heparin fragments are very resistant to biotransformation compared with heparin and endogenous heparin fragments. These fragments may therefore be useful in defining structure activity relationships in vivo.
Details
- Title: Subtitle
- Resistance of heparinase-derived heparin fragments to biotransformation
- Creators
- Annette K Larsen - Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139Kevin G RiceRobert J LinhardtGerald WoganRobert Langer
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.264(3), pp.1570-1577
- DOI
- 10.1016/S0021-9258(18)94225-0
- PMID
- 2912974
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- United States
- Grant note
- HL 29797-04 / NHLBI NIH HHS GM 25810 / NIGMS NIH HHS
- Language
- English
- Date published
- 01/25/1989
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984065501802771
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