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Research ArticleArticle

Aldose Reductase Catalyzes the Oxidation of Naphthalene-1,2-Dihydrodiol for the Formation ofOrtho-Naphthoquinone

Katsumi Sugiyama, Tao-Chin Lin Wang, John T. Simpson, Libaniel Rodriguez, Peter F. Kador and Sanai Sato
Drug Metabolism and Disposition January 1999, 27 (1) 60-67;
Katsumi Sugiyama
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Tao-Chin Lin Wang
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John T. Simpson
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Libaniel Rodriguez
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Peter F. Kador
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Sanai Sato
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Abstract

The oxidation of naphthalene-1,2-dihydrodiol (ND) too-naphthoquinone (NQ) in the lens is believed to be responsible for the formation of cataracts in naphthalene-fed rats. Studies using either recombinant rat lens (RLAR) or human muscle aldose reductase (HMAR) incubated in vitro with ND in the presence of NAD(P) verified that aldose reductase (EC 1.1.1.21) is the dihydrodiol dehydrogenase that catalyzes the oxidation of ND to NQ. Kinetic studies of Vmax/Kmindicated that RLAR catalyzes the NAD-dependent oxidation of ND with an optimal pH of 9.0. The corresponding activity of HMAR was lower than that of rat enzyme. The metabolite produced by the incubation of RLAR with ND in the presence of 2-mercaptoethanol and NAD in 20 mM phosphate buffer, pH 7.5, was isolated by C18 reversed-phase high-performance liquid chromatography. The elution profile showed the formation of a new peak that was identical with a peak generated when NQ was incubated under the same condition. The metabolite in both peaks was identified as 4-(2-hydroxyethylsulfanyl)-1,2-dihydro-1,2-naphthalenedione (HNQ) by1H and 13C NMR analyses using homonuclear correlation spectroscopy , heteronuclear multiple quantum coherence, and heteronuclear shift correlations via multiple bond connectivities as well as infrared analysis. HNQ is readily autoxidized to 2,3-dihydro-1-oxa-4-thia-9,10-phenanthrenedione. The stoichiometry of 1:1 between the consumption of ND and the formation of NADH for the formation of HNQ implies that rat lens aldose reductase catalyzes a 2e− oxidation of ND to yield the corresponding ketol, which is autoxidized to NQ.

Footnotes

  • Send reprint requests to: Dr. Sanai Sato, Laboratory of Ocular Therapeutics, NEI, NIH, Bldg 10, Rm 10B09, 10 Center Drive, MSC 1850, Bethesda, MD 20892-1850. E-mail: sanai{at}helix.nih.gov

  • Abbreviations used are::
    ND
    naphthalene-1,2-dihydrodiol
    NQ
    naphthoquinone
    DMSO
    dimethylsulfoxide
    TLC
    thin layer chromatography
    RLAR
    recombinant rat lens aldose reductase
    HMAR
    recombinant human muscle aldose reductase
    HPLC
    high-performance liquid chromatography
    LC
    liquid chromatography
    ARI
    aldose reductase inhibitors
    EI
    electron ionization
    MS
    mass spectrometry
    COSY
    homonuclear correlation spectroscopy
    HMQC
    heteronuclear multiple quantum coherence
    HMBC
    heteronuclear shift correlations via multiple bond connectivities
    IR
    infrared
    • Received June 8, 1998.
    • Accepted August 31, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (1)
Drug Metabolism and Disposition
Vol. 27, Issue 1
1 Jan 1999
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Research ArticleArticle

Aldose Reductase Catalyzes the Oxidation of Naphthalene-1,2-Dihydrodiol for the Formation ofOrtho-Naphthoquinone

Katsumi Sugiyama, Tao-Chin Lin Wang, John T. Simpson, Libaniel Rodriguez, Peter F. Kador and Sanai Sato
Drug Metabolism and Disposition January 1, 1999, 27 (1) 60-67;

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Research ArticleArticle

Aldose Reductase Catalyzes the Oxidation of Naphthalene-1,2-Dihydrodiol for the Formation ofOrtho-Naphthoquinone

Katsumi Sugiyama, Tao-Chin Lin Wang, John T. Simpson, Libaniel Rodriguez, Peter F. Kador and Sanai Sato
Drug Metabolism and Disposition January 1, 1999, 27 (1) 60-67;
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