Comparison of the mutagenic responses of mismatch repair-proficient (TK6) and mismatch repair-deficient (MT1) human lymphoblast cells to the food-borne carcinogen PhIP.
Heterocyclic amines are ubiquitously present in cooked meats and fish. They represent an important class of food-borne carcinogens. We describe the cytotoxic, apoptotic, and mutagenic responses of mismatch repair-proficient (TK6) and mismatch repair-deficient (MT1) human lymphoblastoid cells to PhIP, the most abundant heterocyclic amine. Dose-dependent increases in cytotoxicity, in apoptosis, and in mutant fractions at the hprt locus were observed following PhIP treatment. We present a statistical method that is useful for comparing two populations. With this method, we show that the data fitted a model that assumes that the PhIP-induced mutation rate is dependent on the cell line. Estimated rates of increase of 22.8 x 10(-6) and 2.2 x 10(-6) mutation per cell per microg PhIP were found in MT1 and TK6, respectively, showing that MT1 is hypermutable to PhIP. MT1 also exhibited lower PhIP-induced apoptosis. We conclude from these results that mismatch repair-deficient cells are hypermutable to the food-borne carcinogen PhIP and that the PhIP-DNA adducts, when not eliminated by apoptosis, can be transformed into mutations.
Leong-Morgenthaler
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Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland. phaikmooi.morgenthaler-leong@ipharm.unil.ch
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D000704:Analysis of Variance; D020137:Base Pair Mismatch; D002273:Carcinogens / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation
D002273:Carcinogens; D007093:Imidazoles; D009153:Mutagens; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine