Abstract
Colchicine is a toxic alkaloid known for its therapeutic applications. In addition to the inhibition of microtubule polymerization, colchicine has been reported to inhibit many key enzymes. Here we provide evidence for colchicine binding and inhibiting ζ-crystallin purified from camel eye lens. Indeed, we demonstrated the molecular interaction between colchicine and ζ-crystallin using fluorescence quenching. Moreover, colchicines inhibited ζ-crystallin activity with respect to two different substrates 9,10-phenanthrenequinone (PQ) and 1,2-Naphthoquinone (NQ) as well as NADPH as coenzyme. The inhibition was time-independent but concentration-dependent with an IC50 value of 1.52 ± 0.055 μM. NADPH was able to protect 38% of enzyme activity against colchicine whereas ζ-crystallin substrates protected only 12-16%. Kinetic analysis revealed that colchicine-induced inhibition of ζ-crystallin activity was non-competitive and uncompetitive with respect to PQ/NQ and NADPH, respectively. In addition, the kinetic analyses along with the protection assay clearly suggest that the binding of colchicine to ζ-crystallin occurs at or close to NADPH binding site. Our data reveal for the first time the inhibitory effect of colchicine on the oxidoreductase activity of camel lens ζ-crystallin illustrating the diversity of colchicine-targeted enzymes. Finally, our findings are of great importance in therapy since ζ-crystallin is known to play a key role in the detoxification processes. Therefore, a particular attention should be taken during colchicine-based therapies to avoid kidney injury and cataract formation.
Keywords: ζ-crystallin, colchicine, NADPH, oxidoreductase, quinone.
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