Inhibition of thioredoxin reductase by lanthanum chloride

Lanthanum chloride (LaCl3) is a good inhibitor of both the cytosolic and mitochondrial thioredoxin reductase with IC50 values of 1.75 and 7.46 μM, respectively. On the contrary, the related enzyme glutathione reductase is not inhibited by lanthanum ions even at relatively high concentrations. In the presence of LaCl3, steady-state kinetics shows a non-competitive type of inhibition with 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) as a substrate suggesting no interaction of this ion with the thiol/selenol active site of thioredoxin reductase. Comparison of the electrostatic surface potential of thioredoxin reductase shows that the presence of a trivalent cation such as La3 + decreases the negatively charged area of the enzyme surface particularly in the region closed to the NADPH binding site. Human ovarian carcinoma cells (A2780 cells) incubated with lanthanum ions show a noticeable inhibition of thioredoxin reductase activity indicating the ability of this ion to reach the active site of the enzyme even in a cellular setting. In addition, A2780 cells treated with LaCl3 show an increase in reactive oxygen species production in part dependent on thioredoxin reductase inhibition.

Lanthanum chloride inhibits both the cytosolic and mitochondrial thioredoxin reductase, while glutathione reductase is completely insensitive. Comparison of the electrostatic surface potential suggests that the presence of a trivalent cation such as La3 + (right) increases the positively charged area (blue) in a region closed to the NADPH binding site of the enzyme surface.Figure optionsDownload as PowerPoint slideHighlights
► LaCl3 inhibits the cytosolic and mitochondrial thioredoxin reductase.
► The cytosolic isoform is more sensitive to LaCl3 than the mitochondrial one.
► In contrast, glutathione reductase is not inhibited by LaCl3.
► A2780 cells, treated with LaCl3, produce reactive oxygen species.