Opposing – Activating or Inhibitory – Effects of Cimetidine and Daidzein on Human ADH1C Activity Depending on Substrates and Solvents
Toxification of benzylic alcohols (e.g. hydroxymethylpyrenes) by sulfotransferases is efficiently competed by
alcohol dehydrogenases (ADHs). We are interested in drugs and food constituents affecting this detoxification. Daidzein
and cimetidine were reported to inhibit ADH1C-mediated ethanol oxidation. Surprisingly, we found that both modulators
enhance the oxidation of 4-hydroxymethylpyrene by ADH1C. This activation was seen with either delivering solvents
used, dimethylsulfoxide or acetonitrile. Addition of dimethylsulfoxide, but not acetonitrile, converted daidzein and
cimetidine from inhibitors to activators of the ADH1C-mediated oxidation of the other substrate studied, ethanol (added in
water). Other human ADH forms (ADH2, 3, 4) were inhibited by both agents independently of the substrate and the
corresponding solvent used. Kinetic constants for the various reactions are presented. ADH1C was unique in its complex
substrate-dependent interaction with daidzein/cimetidine and solvents.
Keywords: ADH1C, cimetidine, daidzein, hydroxymethylpyrene, enzyme inhibition, enzyme activation.
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