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http://hdl.handle.net/11375/7579
Title: | Studies on the Activation of Nitrofurans |
Authors: | Ramcharitar, Sharon Shyama |
Advisor: | McCalla, D.R. |
Department: | Biochemistry |
Keywords: | Biochemistry;Biochemistry |
Publication Date: | Sep-1980 |
Abstract: | <p>Nitrofurans, initially developed in the 1940's as antibacterial agents, have recently been shown to have mutagenic and carcinogenic effects. Nitrofurans exert such effects after metabolism by bacterial and mammalian nitroreductases to produce short-lived, electrophilic intermediates which react with nucleophilic centres of protein and DNA. To characterise the putative intermediates of nitrofurazone, an in vitro activation system was used in which synthetic L-lysine peptides were used to trap the reactive species. Present studies indicate that a small amount of binding of 'activated' nitrofurazone to lysine does occur but the amount of adducts formed is insufficient to permit structural analysis.</p> <p>The bacterial nitroreductases are of two types: type I nitroreductase is active under aerobic conditions while type II is active only under hypoxic conditions. Analysis of crude extracts of type I reductase of wildtype and mutant strains of E. coli K12 by chromatography on DEAE-cellulose has resulted in the separation of three distinct activities which catalyse the reduction of nitrofurans probably by different enzymatic pathways. Two of the activities were previously identified but the third is apparently inactivated by MnCl₂ which has been used as a partial purification step in the past.</p> <p>The mutagenic potencies of nitrofurans vary over a wide range: for the four nitrofurans, AF₂, ANFT, furazolidone and nitrofurazone, there is an 500-fold difference between the strongest and weakest mutagen. The overall rate of reduction and the kinetic constants of the type I nitroreductases with the four nitrofurans as substrates do not vary by more than a factor of three and thus cannot account for the observed differences in mutagenicity, however, the stronger mutagens do produce a larger yield of macromolecule-nitrofuran adducts than the weaker mutagens. Therefore, mutagenicity appears to be related to the stability and electrophilicity of the 'activated' nitrofurans.</p> |
URI: | http://hdl.handle.net/11375/7579 |
Identifier: | opendissertations/2848 3854 1412435 |
Appears in Collections: | Open Access Dissertations and Theses |
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fulltext.pdf | 4.01 MB | Adobe PDF | View/Open |
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