Mode of transport and possible mechanism of action of L-phenylalanine benzyl ester as an anti-sickling agent.
L-Phenylalanine benzyl ester (Phe-Bz) and a number of ester analogues prevent sickling of erythrocytes from sickle cell disease patients. The compounds tested exhibit anti-sickling activity in the concentration range 0.5-3.0 mM. A general feature of these compounds is the presence of two aromatic rings in their molecular structure. The anti-sickling agents rapidly enter the erythrocyte and are hydrolysed to their component molecules. Incubation of human erythrocytes with 3.0 mM L-phenylalanine for 30 min at 37 degrees C results in accumulation of 2.0 mmol L-phenylanine/l cells, while incubation of erythrocytes with 3.0 mM Phe-Bz under similar conditions results in the production of 4.0 mmol L-phenylalanine/l cells and an equivalent amount of benzyl alcohol. Both L-phenylalanine and benzyl alcohol are inhibitors of the gelation of deoxyhaemoglobin S (deoxy-HbS) in vitro. Moreover, Phe-Bz and related anti-sickling agents fluidize the lipid bilayer of the erythrocyte membrane, inhibiting several transport systems, including those for L-phenylalanine, uridine and sulphate ions, as well as the Na+ pump and the Na+/K+ cotransporter, but increasing the passive influx and efflux of both cations and anions. The accumulation of Phe-Bz hydrolysis products within the erythrocyte together with the effects of Phe-Bz on cation permeability result in the influx of water causing the cell to swell. Thus, treatment of erythrocytes with 3.0 mM Phe-Bz at 37 degrees C for 30 min causes an increase in mean cell volume of 14.8%, decreasing the mean intracellular haemoglobin concentration from 34 to 29.6 g%. The increase in cell volume caused by Phe-Bz and its analogues together with the direct effects of their hydrolysis products on HbS probably act in concert to bring about the anti-sickling effect.
D000755:Anemia, Sickle Cell / Q000097:blood*; D000986:Antisickling Agents / Q000097:blood*; D001692:Biological Transport; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000986:Antisickling Agents; D010649:Phenylalanine; C023629:phenylalanine O-benzyl ester