Inhibition of thioredoxin reductase by lanthanum chloride.
Lanthanum chloride (LaCl(3)) is a good inhibitor of both the cytosolic and mitochondrial thioredoxin reductase with IC(50) 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 LaCl(3), 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 La(3+) 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 LaCl(3) show an increase in reactive oxygen species production in part dependent on thioredoxin reductase inhibition.
Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35131 Padova, Italy.
Anna
A
Citta
Alessandra
A
Folda
Guido
G
Scutari
Luca
L
Cesaro
Alberto
A
Bindoli
Maria Pia
MP
Rigobello
D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D004228:Dithionitrobenzoic Acid / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007811:Lanthanum / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D017382:Reactive Oxygen Species; C028521:lanthanum chloride; D007811:Lanthanum; D004228:Dithionitrobenzoic Acid; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase