Uptake of N-(4'-pyridoxyl)amines and release of amines by renal cells: a model for transporter-enhanced delivery of bioactive compounds
| Autor: | Donald B. McCormick, Zuomin Zhang |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Male
Stereochemistry In Vitro Techniques Kidney Tubules Proximal chemistry.chemical_compound medicine Animals Amines Pyridoxal Biotransformation chemistry.chemical_classification Oxidase test Multidisciplinary Molecular Structure Pyridoxine Biological Transport Rats Inbred Strains Membrane transport Pyridoxal kinase Rats Kinetics Enzyme chemistry Amine gas treating Pyridoxamine Carrier Proteins Research Article medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 88:10407-10410 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.88.23.10407 |
| Popis: | The importing of vitamin B6 by renal proximal tubular cells from the rat is facilitated and Na(+)-dependent and reflects specificity for the meta-phenolate pyridinium structure with a 5-hydroxymethyl function. This transporter can, however, accept competitively each of the natural nonphosphorylated vitamers (pyridoxine, pyridoxamine, and pyridoxal) and other B6 analogues differing only in the groups at position 4. A series of N-(4'-pyridoxyl)amines was synthesized by sodium borohydride or boro[3H]hydride reduction of aldimines formed by condensing the amines with pyridoxal. The unlabeled B6-secondary amine compounds were found to competitively inhibit the uptake of [4'-3H]pyridoxine by the renal cells. Moreover, the 3H-labeled N-(4'-pyridoxyl)amines were shown to enter the cells by the process facilitated by the B6 transporter. Upon entry the labeled compounds were converted to N-(5'-phospho-4'-pyridoxyl)amines in a reaction catalyzed by pyridoxal kinase, an enzyme that tolerates considerable functional variation in position 4 of the B6 structure. The 5'-phosphates were subsequently converted within the cell to pyridoxal 5'-phosphate with liberation of the original amine in a reaction catalyzed by pyridoxamine (pyridoxine) 5'-phosphate oxidase, an enzyme with broad specificity for 4'-substituted amines on the 5'-phospho-B6 structure. This system illustrates how knowledge of transporter specificity can permit design of a compound with potential biologic activity. A drug or other intracellular effector may be piggybacked onto a transported solute (e.g., vitamin or other nutrient) that gains facilitated entry to a cell and is, thereafter, metabolized to release the active compound. |
| Databáze: | OpenAIRE |
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