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Mol Biochem Parasitol. 2008 Jul;160(1):65-9. doi: 10.1016/j.molbiopara.2008.03.006. Epub 2008 Mar 21.

Cytotoxic interactions of methylene blue with trypanosomatid-specific disulfide reductases and their dithiol products.

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1
Biochemie-Zentrum der Universit├Ąt Heidelberg, INF 504, D-69120 Heidelberg, Germany.

Abstract

Methylene blue (MB) is known to have trypanocidal activity. We tested the interactions of MB with a number of trypanosomatid-specific molecules of the antioxidant metabolism. At pH 7, trypanothione and other (di)thiols were oxidized to disulfides by the phenothiazine drug. MB inhibited Trypanosoma cruzi trypanothione reductase (TR) (K(i)=1.9 microM), and served as a significant subversive substrate of this enzyme (K(M)=30 microM, k(cat)=4.9s(-1)). With lipoamide dehydrogenase, the second thiol-generating flavoenzyme of T. cruzi, the catalytic efficiency for MB reduction was found to be almost 10(6)M(-1)s(-1). When the system MB-enzyme-molecular oxygen acts as a NAD(P)H-driven redox cycler, a reactive oxygen species, H(2)O(2) or superoxide, is produced in each cycle. Since MB is an affordable, available, and accessible drug it might be tested--alone or in drug combinations--against trypanosomatid-caused diseases of animal and man.

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