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Killing and Mutation of Human Lymphoblast Cells by Aflatoxin B₁: Evidence for an Inducible Repair Response¹

Department of Applied Biological Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Diploid human lymphoblast cells exhibit apparent saturation of mutation induced by exposure to aflatoxin B₁, 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 biphasic nature of aflatoxin-DNA adduct loss in vivo shows initial, rapid removal of all adduct species, followed by a slow loss of the aflatoxin-N⁷-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-N⁷-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.

¹ Supported by Department of Energy Contract DE-AC-EV04267, National Institute of Environmental Health Sciences Grant NIH-5-P01-ES00597, and NIH Training Grant NIH-5-T32-ES07020-07.

² Present address: Dana Farber Cancer Institute, Boston, MA 02115.

³ Present address: Cancer Research Center, Massachusetts Institute of Technology, Cambridge, MA 02139.

⁴ Present address: Biology Department, Yale University, New Haven, CT 06520.

⁵ Present address: Department of Chemistry, Harvard University, Cambridge, MA 02138.

⁶ To whom requests for reprints should be addressed, at Department of Applied Biological Sciences, Room E18-666, Massachusetts Institute of Technology, Cambridge, MA 02139.

Received 5/29/86. Revised 10/ 7/86. Revised 12/31/86. Accepted 1/ 7/87.