Opposing – Activating or Inhibitory – Effects of Cimetidine and Daidzein on Human ADH1C Activity Depending on Substrates and Solvents

Ronny      Kollock; Hansruedi      Glatt

Abstract

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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