Uptake of N-(4 prime -pyridoxyl)amines and release of amines by renal cells: A model for transporter-enhanced delivery of bioactive compounds

Journal Article · Sun Dec 01 04:00:00 EST 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.23.10407· OSTI ID:5604958

Zhang, Zuomin; McCormick, D B ^[1]

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1. Emory Univ., Atlanta, GA (United States)

The importing of vitamin B{sub 6} by renal proximal tubular cells from the rat is facilitated and Na{sup +}-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 non-phosphorylated vitamers (pyridoxine, pyridoxamine, and pyridoxal) and other B{sub 6} analogues differing only in the groups at position 4. A series of N-(4{prime}-pyridoxyl)amines was synthesized by sodium borohydride or boro({sup 3}H)hydride reduction of aldimines formed by condensing the amines with pyridoxal. The unlabeled B{sub 6}-secondary amine compounds were found to competitively inhibit the uptake of (4{prime}-{sup 3}H)pyridoxine by the reenal cells. Moreover, the {sup 3}H-labeled N-(4{prime}pyridoxyl)amines were shown to enter the cells by the process facilitated by the B{sub 6} transporter. Upon entry the labeled compounds were converted to n-(5{prime}-phospho-4{prime}-pyridoxyl)amines in a reaction catalyzed by pyridoxal kinase, an enzyme that tolerates considerable functional variation in position 4 of the B{sub 6} structure. The 5{prime}-phosphates were subsequently converted within the cell to pyridoxal 5{prime}-phosphate with liberation of the original amine in a reaction catalyzed by pyridoxamine (pyridoxine) 5{prime}-phosphate oxidase, an enzyme with broad specificity for 4{prime}-substituted amines on the 5{prime}-phospho-B{sub 6} 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.

• OSTI ID: 5604958
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Vol. 88:23; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

550200* -- Biochemistry
59 BASIC BIOLOGICAL SCIENCES
ALDEHYDES
AMINES
AZINES
BODY
CHROMATOGRAPHY
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
ION EXCHANGE CHROMATOGRAPHY
KIDNEYS
MEMBRANE TRANSPORT
METABOLISM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PHYSIOLOGY
PYRIDINES
PYRIDOXAL
SEPARATION PROCESSES
TRITIUM COMPOUNDS