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.