Enzymatic reduction of sulphoxide-containing xenobiotics by the intestinal microflora
Enzymatic reduction of sulphoxide-containing xenobiotics by the intestinal microflora
Reduction of the sulphoxide group of xenobiotics has been studied in the caecal contents of the rat and the intestinal microflora using ten substrates (sulindac, methylphenyl sulphoxide, methyl-p-tolyl sulphoxide (R and S forms), phenylvinyl sulphoxide, phenyl sulphoxide, benzyl sulphoxide, benzylphenyl sulphoxide, ethylphenyl sulphoxide and butyl sulphoxide). Those sulphoxides not available were chemically synthesised from their sulphides. The reduction of other functional groups (nitro and azido) to their corresponding amino groups by the intestinal microflora has also been investigated.
Extensive reduction was observed of all of the sulphoxides when incubated with rat caecal contents under anaerobic conditions. Methylphenyl sulphoxide, methyl-p-tolyl sulphoxide (R and S forms), and phenylvinyl sulphoxide all underwent significant reduction, with lesser reduction observed with the bulkier substrates such as benzyl sulphoxide, benzylphenyl sulphoxide and phenyl sulphoxide.
Escherichia coli BM1023 isolated from human faeces demonstrated extensive reduction of sulindac in the presence of dithiothreitol (DTT) as a cofactor. Reductases in both the cytosol and membrane fraction were responsible for the reduction of sulphoxides to the sulphides, requiring NADH/NADPH and/or DTT as cofactors. The cytosol fraction did not reduce benzyl sulphoxide and benzylphenyl sulphoxide and the membrane fraction did not reduce phenylvinyl sulphoxide or butyl sulphoxide.
Further purification of the cytosol fraction using precipitation by ammonium sulphate and DEAE cellulose chromatography have revealed that multiple enzyme systems are responsible for the reduction of sulphoxides. Of the ten sulphoxides substrates selected five were reduced by the purified enzyme fractions. Reduction of sulindac and methylphenyl sulphoxide was dependent on the presence of thioredoxin together with NADH or NADPH as cofactors. Methyl-p-tolyl sulphoxide (R form) did not require the presence of thioredoxin, which actually inhibited the enzyme reducing this substrate. Similarly enzyme systems reducing phenyl sulphoxide did not require the presence of thioredoxin.
University of Southampton
1996
Grewal, Harinder Kaur
(1996)
Enzymatic reduction of sulphoxide-containing xenobiotics by the intestinal microflora.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Reduction of the sulphoxide group of xenobiotics has been studied in the caecal contents of the rat and the intestinal microflora using ten substrates (sulindac, methylphenyl sulphoxide, methyl-p-tolyl sulphoxide (R and S forms), phenylvinyl sulphoxide, phenyl sulphoxide, benzyl sulphoxide, benzylphenyl sulphoxide, ethylphenyl sulphoxide and butyl sulphoxide). Those sulphoxides not available were chemically synthesised from their sulphides. The reduction of other functional groups (nitro and azido) to their corresponding amino groups by the intestinal microflora has also been investigated.
Extensive reduction was observed of all of the sulphoxides when incubated with rat caecal contents under anaerobic conditions. Methylphenyl sulphoxide, methyl-p-tolyl sulphoxide (R and S forms), and phenylvinyl sulphoxide all underwent significant reduction, with lesser reduction observed with the bulkier substrates such as benzyl sulphoxide, benzylphenyl sulphoxide and phenyl sulphoxide.
Escherichia coli BM1023 isolated from human faeces demonstrated extensive reduction of sulindac in the presence of dithiothreitol (DTT) as a cofactor. Reductases in both the cytosol and membrane fraction were responsible for the reduction of sulphoxides to the sulphides, requiring NADH/NADPH and/or DTT as cofactors. The cytosol fraction did not reduce benzyl sulphoxide and benzylphenyl sulphoxide and the membrane fraction did not reduce phenylvinyl sulphoxide or butyl sulphoxide.
Further purification of the cytosol fraction using precipitation by ammonium sulphate and DEAE cellulose chromatography have revealed that multiple enzyme systems are responsible for the reduction of sulphoxides. Of the ten sulphoxides substrates selected five were reduced by the purified enzyme fractions. Reduction of sulindac and methylphenyl sulphoxide was dependent on the presence of thioredoxin together with NADH or NADPH as cofactors. Methyl-p-tolyl sulphoxide (R form) did not require the presence of thioredoxin, which actually inhibited the enzyme reducing this substrate. Similarly enzyme systems reducing phenyl sulphoxide did not require the presence of thioredoxin.
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Published date: 1996
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Local EPrints ID: 459600
URI: http://eprints.soton.ac.uk/id/eprint/459600
PURE UUID: a9402bee-29ad-4294-ab82-88b5228fe842
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Date deposited: 04 Jul 2022 17:14
Last modified: 04 Jul 2022 17:14
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Author:
Harinder Kaur Grewal
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