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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Prooxidant activity and cytotoxic effects of indole-3-acetic acid derivative radicals.

Previously, it was shown that indole-3-acetic acid (IAA) is a nontoxic prodrug that forms a radical, toxic to tumor cells when activated by peroxidase. Because of this, IAA and peroxidase conjugated to an antibody specific to an extracelluar tumor antigen are currently in phase II clinical trials. In the following, the prooxidant activities of the radicals formed were compared when IAA or its derivatives were metabolically oxidized by peroxidase/H(2)O(2). In general, it was found that the effectiveness of IAA analogues for catalyzing the cooxidation of ascorbate, NADH, or GSH increased as the IAA derivatives were more readily oxidized by HRP/H(2)O(2). The order of effectiveness of IAA derivatives at cooxidizing NADH, ascorbate, GSH, and hepatocyte GSH was 5MeO-2Me-IAA > 2Me-IAA > 5MeO-IAA > IAA. The rates of NADH and ascorbate cooxidation were faster at pH 7.4 than at pH 6.0, whereas GSH cooxidation was faster at pH 6.0 than at pH 7. 4. Furthermore, NADH, ascorbate, and GSH prevented the oxidation of IAA derivatives, which suggested that the indolyl cation radical was responsible for the prooxidant activity. The effectiveness of IAA derivatives in catalyzing lipid peroxidation at pH 7.4 was similar and also correlated with the rate of oxidation of IAA derivatives by HRP-I and the one-electron potential of these compounds. The IAA derivative-induced lipid peroxidation was faster at pH 6.0 than at pH 7. 4. IAA derivative effectiveness at catalyzing microsomal and hepatocyte lipid peroxidation or hepatocyte reactive oxygen species formation at pH 6.0 was IAA > 5MeO-2Me-IAA > 2Me-IAA > 5MeO-IAA, but at pH 7.4, it was 5MeO-2Me-IAA > 2Me-IAA > 5MeO-IAA > IAA. Previously, the rate of radical cation decarboxylation to skatole radicals and (skatole) peroxyl radicals was reported to be faster at an acid pH with IAA being more effective than the derivatives. This suggests that IAA skatole and/or (skatole) peroxyl radicals catalyze lipid peroxidation at pH 6. 0. Incubation of isolated rat hepatocytes with IAA analogues/H(2)O(2)/peroxidase also resulted in cytotoxicity with 5MeO-2Me-IAA being the most effective at pH 7.4 and IAA being the most effective at pH 6. 0. Cytotoxicity was also prevented by antioxidants.[1]

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