Delta-aminolevulinic acid transport in cancer cells of the human extrahepatic biliary duct.

Abstract

This study was performed to characterize the transport of the endogenous photosensitizer delta-aminolevulinic acid in tumor cells of the extrahepatic biliary duct. Uptake of [(3)H]delta-aminolevulinic acid into human cholangiocarcinoma SK-ChA-1 cells was linear for up to 10 min, independent of a Na(+) gradient, but stimulated 3- to 4-fold by an inwardly directed H(+) gradient. Uptake of delta-aminolevulinic acid was mediated by a single transport system with an apparent affinity (K(t)) of 2.1 mM and a maximal velocity (V(max)) of 60.1 nmol. 10 min(-1). mg of protein(-1). Glycylsarcosine, alanylalanine, and cefadroxil strongly inhibited the [(3)H]delta-aminolevulinic acid uptake with K(i) values of 1.3, 0.2, and 3.6 mM, respectively. In contrast, gamma-aminobutyric acid, glycine, L-glutamic acid, and L-aspartic acid (all 10 mM) had no effect on the total [(3)H]delta-aminolevulinic acid uptake, neither at pH 6.0 nor at pH 7.5. Applying a Dixon type of experiment and the ABC test revealed that glycylsarcosine and delta-aminolevulinic acid are transported via the same system, PEPT1. Treatment of the cells with phorbol 12-myristate 13-acetate, a phorbol ester that activates protein kinase C, resulted in a significant inhibition of the transport rate. This inhibition could be blocked by cotreatment with staurosporine. We conclude that delta-aminolevulinic acid is transported by the H(+)/peptide cotransporter PEPT1 into epithelial cells of the extrahepatic biliary duct. delta-Aminolevulinic acid can be accumulated specifically in bile duct tumor cells before photodynamic therapy.

• Authors: Jana Neumann, Matthias Brandsch
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 305 Issue 1 Pg. 219-24 (Apr 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12649372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Peptide Transporter 1
• Phorbol Esters
• SLC15A1 protein, human
• Symporters
• Aminolevulinic Acid

Topics

• Aminolevulinic Acid (metabolism)
• Bile Ducts, Extrahepatic (drug effects, metabolism, pathology)
• Biological Transport (drug effects)
• Carrier Proteins (metabolism)
• Humans
• Kinetics
• Peptide Transporter 1
• Phorbol Esters (pharmacology)
• Symporters
• Tumor Cells, Cultured