Killing and Mutation of Human Lymphoblast Cells by Aflatoxin B,: Evidence for an Inducible Repair Response1

Diploid human lymphoblast cells exhibit apparent saturation of mu tation induced by exposure to aflatoxin B,, despite a linear increase in the amount and proportion of the aflatoxin-DNA adducts formed. The saturation is neither a cell cycle phenomenon nor a result of a genetically heterozygous population. Examination of the hiphasic nature of aflatoxinDNA adduct loss in vivoshows initial, rapid removal of all adduct species, followed by a slow loss of the aflatoxin-A/7-guanine adduct alone. We hypothesize that these data reveal two modes of adduct loss in these cells. The first is an inducible, error-free system that is short-lived, turning off as adduct levels fall below the induction threshold of some 1000 total adducts/cell. The second loss is slower and results from spontaneous depurination of remaining aflatoxin-A^-guanines. Our data are in agreement with the possibility that apurinic sites thus generated are responsible for the mutation observed. A major paradox arises from the fact that aflatoxin-related premutagenic depurinations are estimated to be only 10% of the number of spontaneous depurinations estimated by others to occur in human cells in a 1-h period.