Prostaglandin synthase and horseradish peroxidase catalyzed DNA-binding of p-phenetidine

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Abstract
The prostaglandin synthase and horseradish peroxidase catalyzed binding of p -phenetidine to DNA was investigated. The addition of arachidonic acid to an incubation containing ram seminal vesicle microsomes, [ 14 C] p -phenetidine and DNA resulted in a rapid incorporation of radioactivity into DNA. This was inhibited by >75% by indomethacin (0.1 mM) or butylated hydroxyanisole (0.5 mM). Hydrogen peroxide was as efficient as arachidonic add in mediating the activation of p -phenetidine thus implicating the involvement of the hydroperoxidase activity of prostaglandin synthase in this reaction. Horseradish peroxidase and hydrogen peroxide also catalyzed the activation of p -phenetidine to DNA-binding metabolites. Reduced glutathione (GSH) stimulated the binding of p -phenetidine to DNA by >3-fold in both the prostaglandin synthase and the horseradish peroxidase system, whereas cysteine and N-acetylcysteine reduced the DNA-binding in the prostaglandin synthase system by up to 62% under the conditions used. Furthermore, water-soluble metabolites formed in the presence of GSH also bound to DNA. Seventy-two hour dialysis of DNA samples from incubations with GSH present reduced the amount of bound material by 75%. In contrast, the radioactivity which associated with DNA in the absence of GSH was not decreased by dialysis.

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