The benzamide derivative metoclopramide causes DNA damage and inhibition of DNA repair in human peripheral mononuclear leukocytes at clinically relevant doses.
The polysubstituted benzamide derivative metoclopramide (MCA) has previously been shown to enhance the effect of cisplatin and ionizing radiation treatment of xenografted human squamous cell carcinomas from the head and neck region. In the present work we show that MCA decreases the nucleoid sedimentation rate, indicating that MCA causes strand breaks in the DNA of human peripheral mononuclear leukocytes treated in vitro. This effect is seen with MCA in the dose range from 100 nM to 1 mM. MCA also stimulated the activity of the enzyme adenosine-diphospho-ribosyl transferase both in cells treated with MCA alone, and in combination with 15 Gy. This was taken as additional evidence that MCA causes DNA strand breaks. The DNA damage induced by MCA was poorly repaired when assessed by nucleoid sedimentation analysis, and this effect on repair was confirmed by showing that MCA also inhibits N-acetoxy-2-acetylaminofluorene-induced unscheduled DNA synthesis. The effect of MCA on DNA damage measured by nucleoid sedimentation has also been demonstrated in permeabilized cells. These data indicate that the DNA-damaging effect of MCA is not dependent on surface receptors or cytoplasmic processes.
Lybak
S
S
Department of Molecular Ecogenetics, University of Lund, Sweden.
Pero
R W
RW
D000099:Acetoxyacetylaminofluorene / Q000633:toxicity; D000228:Adenine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D008787:Metoclopramide / Q000633:toxicity*
D000099:Acetoxyacetylaminofluorene; D000228:Adenine Phosphoribosyltransferase; D008787:Metoclopramide