Inhibition of DNA synthesis and alteration to DNA structure by the phenacetin analog p-aminophenol.
p-Aminophenol a structural analog and minor metabolite of phenacetin has previously been shown to be a potent nephrotoxic agent. In this report we have shown that p-aminophenol has a marked effect on DNA function and structure. DNA synthesis was inhibited in a dose-dependent manner in human lymphoblastoid cells after exposure to p-aminophenol. Results suggest that DNA synthesis is inhibited by the action of p-aminophenol on DNA structure. At low concentrations of p-aminophenol a reduction in the degree of supercoiling of cellular DNA is observed, as determined by sedimentation under neutral conditions. However at higher concentrations an increase in sedimentation of nucleoids (supercoiled molecules) is obtained which is indicative of an increased level of supercoiling or a more compact structural form of DNA due to folding or aggregation. The number of single strand breaks in DNA, when determined by sedimentation in alkaline sucrose gradients, increases with increasing dose of p-aminophenol. The increase in strand breakage observed at lower concentrations of p-aminophenol agrees with the reduced sedimentation rate obtained under neutral conditions. At higher concentrations of p-aminophenol the extent of breakage of DNA increases under alkaline conditions but an increase in sedimentation occurs under neutral conditions.
D000627:Aminophenols / Q000494:pharmacology*; D002478:Cells, Cultured; D002499:Centrifugation, Density Gradient; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism
D000627:Aminophenols; D004247:DNA; C026729:4-aminophenol