Date

2008

Author

Karakurt, Serdar

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Cancer is the second leading cause of death after cardiovascular diseases in the world. Many of the chemical carcinogens need metabolic activation that catalyzed by cytochrome P450 and Phase II enzymes in order to exert their genotoxic and carcinogenic effects. Hence one possible mechanism is that phenolic compounds may alter anticarcinogenic effects is through an interaction with these enzymes either by the inhibition or activation of certain forms, leading to a reduced production of the ultimate carcinogen. Therefore anti-carcinogen activity of tannic acid, a hydrolyzable plant polyphenol, has a crucial importance to prevent conversion of pro-carcinogens to their carcinogenic form. Tannic acid is produced from secondary metabolism of plants and is found in edible vegetables, fruits and nuts, especially tea, cocoa, coffee and wine. In the present work, modulation of rabbit liver and kidney microsomal P450 dependent aniline 4-hydroxylase, N-nitrosodimethylamine N-demethylase and p-nitrophenol hydroxylase activities and cytosolic phase II enzymes; glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase:1 (NQO1) were studied in the presence of tannic acid at concentrations ranging from 0.5 M to 150 M in the reaction medium. The results obtained in this study were shown that tannic acid significantly inhibited the activities of p-nitrophenol hydroxylase, aniline 4-hydroxylase, NDMA N-demethylase, glutathione S-transferase, NAD(P)H:quinine oxidoreductase 1. Tannic acid was found to be the most potent inhibitor of cytosolic glutathione S-transferase with IC50 of 0.33 M and the least potent inhibitor of microsomal aniline 4-hydroxylase.with IC50 of 60.26 M. Effect of tannic acid on enzyme activities was further studied for both mode and type of inhibition. For this purpose various concentrations of the substrate were examined at various tannic acid concentrations. Lineweaver-Burk and Dixon plots were then generated from the resulting data sets. The Km value and inhibition constants (KI) were determined from double reciprocal and Dixon plot of the enzyme activity versus substrate and inhibitor concentration, respectively. Tannic acid was shown to be a noncompetitive inhibitor for liver cytosolic GST, NQO1 and microsomal aniline 4- hydroxylase enzymes with KI of 0.3 M, 41 M and 54.7 M, respectively. On the other hand, in kidney tissues, tannic acid was an uncompetitive inhibitor of cytosolic GST, while it was noncompetitive inhibitor for cytosolic NQO1 with a KI of 12.6 M. These results indicate that tannic acid may modulate cytochrome P450 dependent and Phase II enzymes and influence the metabolic activation of xenobiotics mediated by these enzymes.

Subject Keywords

Biochemistry., Tannic acid., Cytochrome P450., Phase II.

URI

http://etd.lib.metu.edu.tr/upload/12609635/index.pdf
https://hdl.handle.net/11511/17816

Collections

Graduate School of Natural and Applied Sciences, Thesis