Aldose reductase catalyzes the oxidation of naphthalene-1,2-dihydrodiol for the formation of ortho-naphthoquinone

Katsumi Sugiyama, Tao Chin Lin Wang, John T. Simpson, Libaniel Rodriguez, Peter F. Kador, Sanai Sato

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Abstract

The oxidation of naphthalene-1,2-dihydrodiol (ND) to o-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 V(max)/K(m) indicated 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) by 1H 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.

Original languageEnglish (US)
Pages (from-to)60-67
Number of pages8
JournalDrug Metabolism and Disposition
Volume27
Issue number1
StatePublished - Jan 1 1999

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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