Comparison of the mutagenic responses of mismatch repair‐proficient (TK6) and mismatch repair‐deficient (MT1) human lymphoblast cells to the food‐borne carcinogen PhIP

AbstractHeterocyclic 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 × 10−6 and 2.2 × 10−6 mutation per cell per μg 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. Environ. Mol. Mutagen. 38:323–328, 2001. © 2001 Wiley‐Liss, Inc.