32P-postlabelling studies on the DNA adducts of the food mutagens/carcinogens IQ and PhIP--adduct formation in a chemical system, and by rat and human metabolism.
The DNA adducts of the food mutagens/carcinogens IQ and PhIP were studied by means of 32P-postlabelling techniques. Adducts were generated in vitro and in vivo by three techniques: by photolysis of azido-IQ and azido-PhIP in the presence of dGp, calf-thymus DNA or Salmonella; by administration of IQ and PhIP to rats; and by incubation of cultured COS-1 cells with IQ. These cells expressed the human cytochromes P450 1A1 or P450 1A2 and/or the human N-acetyltransferases NAT1 or NAT2. The data demonstrate that, in the photolytic, rat and human systems, a common IQ metabolite and a common PhIP metabolite are formed together with common sets of IQ adducts and PhIP adducts. The data obtained in the human system show that N-hydroxy-IQ, formed by cytochrome P450, binds poorly to DNA, whereas more efficient binding occurs in the presence of NAT1 and most efficient binding in presence of NAT2. This indicates an O-acetyltransferase activity of human NAT1 and NAT2 and formation of N-acetoxy-IQ as an intermediate and immediate precursor of the ultimate arylnitrenium ion. The effect of the polymorphic NAT2 suggests a critical role for the human acetylation polymorphism in the DNA-binding of IQ in humans and in its genotoxic implications.
Kerdar
R S
RS
Institute of Toxicology, University of Würzburg, Germany.
Fasshauer
I
I
Probst
M
M
Blum
M
M
Meyer
U A
UA
Wild
D
D
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000528:radiation effects / Q000633:toxicity; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000528:radiation effects / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D009153:Mutagens / Q000378:metabolism / Q000528:radiation effects / Q000633:toxicity; D010761:Phosphorus Radioisotopes; D011804:Quinolines / Q000378:metabolism / Q000528:radiation effects / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D014466:Ultraviolet Rays
D002273:Carcinogens; D007093:Imidazoles; D009153:Mutagens; D010761:Phosphorus Radioisotopes; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001191:Arylamine N-Acetyltransferase