Biochemical Studies of a New Class of Alcohol Dehydrogenase Inhibitors from Radix puerariae

Authors

  • Wing-Ming Keung

    Corresponding author
    1. Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
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*Assistant Professor, Center for Biochemical and Biophysical Sciences and Medicine, Harvard 1 Medical School, 250 Longwood Avenue, Boston, MA 02115.

Abstract

Two potent, reversible inhibitors of human alcohol dehydrogenase; (ADH) isozymes were isolated from Radix puerariae (RP, commonly, known as kudzu root) and identified as the isoflavones daidzein and genistein. The 4-methoxy derivatives of daidzein (trivial name, for-mononetin) and genistein (biochanin A), minor constituents of RP, were also shown to be ADH inhibitors. All of these isoflavones inhibit 1 the human -γ1γ2-ADH isozyme competitively with respect to ethanol] and uncompetitively with respect to NAD+. A survey of more than 40 structurally related compounds revealed one more isoflavone (prunetin) and four flavones (7-hydroxyflavone, apigenin, galangin, and kaempferol) that inhibit ADH. The isoflavone inhibitors, however, are far more potent than the flavone inhibitors. Among the isoflavones studied, genistein is the most potent with Ki, = 0.1 μM toward γ2γ2- ADH. Human ADH isozymes differ in their sensitivity to these inhibitors in the order γ2γ2-, γ1γ1 > α1α1,> > xx-ADH. These inhibitors, do not affect the β1β1, and β2β2-ADH isozymes at concentrations as high as 20 μM. Rat and rabbit class I ADHs are also inhibited by these. isoflavone inhibitors. The 7-O-glucosyl derivatives of daidzein, genistein, formononetin, and biochanin A do not inhibit ADH, but are potent aldehyde dehydrogenase inhibitors.

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