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Research ArticleArticle

Biotransformation of Nitroso Aromatic Compounds and 2-Oxo Acids to N-Hydroxy-N-arylacylamides by Thiamine-Dependent Enzymes in Rat Liver

Tadao Yoshioka and Takayoshi Uematsu
Drug Metabolism and Disposition July 1998, 26 (7) 705-710;
Tadao Yoshioka
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Takayoshi Uematsu
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Abstract

The formation of N-hydroxy-N-arylacylamides from nitroso aromatic compounds and 2-oxo acids was investigated using rat liver subcellular fractions. Activities were found in both mitochondria and cytosol, except for activities for phenylpyruvate and glyoxylate; the former did not produceN-hydroxy-N-phenylphenylacetamide and the latter nonenzymatically producedN-hydroxy-N-phenylformamide with nitrosobenzene (NOB). The cytosolic activity ofN-hydroxy-N-phenylglycolamide formation was indicated to be due to transketolase, which utilized hydroxypyruvate as a glycolic aldehyde donor to NOB. With mitochondria, 2-oxo acids (including hydroxypyruvate) served as substrates for the biotransformation of NOB to the correspondingN-hydroxy-N-phenylacylamides. The substrate preference was 2-oxobutyrate > pyruvate > 2-oxoisovalerate > 2-oxoisocaproate > 2-oxovalerate > 2-oxo-3-methylvalerate, judging fromVmax/half-saturating concentration for mitochondria values. The half-saturating concentrations for NOB were nearly constant. The mitochondrial activity was due to pyruvate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex (BCDHC). By using partially purified BCDHC, pyruvate and 2-oxobutyrate were found to be common substrates for both of the enzymes, and 2-oxoisovalerate was shown to be the most effective substrate for BCDHC. Analysis by the Taft equation indicated that the polar effects, rather than the steric effects, of the alkyl groups of 2-oxo acids are important for BCDHC-catalyzed formation ofN-hydroxy-N-phenylacylamides. A positive Hammett constant obtained for the formation ofN-hydroxy-N-arylisobutyramides indicates that an electron-withdrawing substituent makes the nitroso compounds susceptible to BCDHC-catalyzed biotransformation.

Footnotes

  • Send reprint requests to: Dr. T. Uematsu, Department of Chemical Hygiene, Hokkaido Institute of Pharmaceutical Sciences, Otaru 047–02, Japan.

  • Abbreviations used are::
    PDHC
    pyruvate dehydrogenase complex
    BCDHC
    branched-chain 2-oxo acid dehydrogenase complex
    MOPS
    3-morpholinopropanesulfonic acid
    NOB
    nitrosobenzene
    S0.5
    half-saturating concentration for mitochondria
    TPP
    thiamine pyrophosphate
    Me2SO
    dimethylsulfoxide
    Me4Si
    tetramethylsilane
    MeOH
    methanol
    EtOH
    ethanol
    • Received January 21, 1998.
    • Accepted March 24, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 7
1 Jul 1998
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Research ArticleArticle

Biotransformation of Nitroso Aromatic Compounds and 2-Oxo Acids to N-Hydroxy-N-arylacylamides by Thiamine-Dependent Enzymes in Rat Liver

Tadao Yoshioka and Takayoshi Uematsu
Drug Metabolism and Disposition July 1, 1998, 26 (7) 705-710;

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Research ArticleArticle

Biotransformation of Nitroso Aromatic Compounds and 2-Oxo Acids to N-Hydroxy-N-arylacylamides by Thiamine-Dependent Enzymes in Rat Liver

Tadao Yoshioka and Takayoshi Uematsu
Drug Metabolism and Disposition July 1, 1998, 26 (7) 705-710;
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