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Irradiation-induced Expression of O⁶-Methylguanine-DNA Methyltransferase in Mammalian Cells¹

Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03756

O⁶-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which plays an important role in chemotherapy, mutagenesis, and carcinogenesis. The specific activity of MGMT in female rat liver can be induced by approximately 20-fold by treatment of the rats with -irradiation. Maximum response occurred 48 h after 15 Gy irradiation. MGMT levels in male rats were induced by only 3-fold. MGMT activity was also induced by irradiation of rat hepatoma H4IIE cells with a 3-fold increase noted after treatment with 3 Gy. Northern analysis and nuclear run-on assays indicated that the induction of MGMT was regulated at the transcriptional level. The radiation-mediated increase in MGMT was blocked by H7, a protein kinase inhibitor, but not by H89, an inhibitor of protein kinase A. Hydroxyl radicals may play a role in the induction mechanism since dimethyl sulfoxide, a radical scavenger, blocked the radiation-mediated increase in MGMT. MGMT activity was also increased by treatment of the cells with H₂O₂, in accordance with the involvement of activated oxygen species in the induction of MGMT. Finally, the addition of cycloheximide, an inhibitor of protein synthesis, prior to but not after irradiation, abolished the increase in MGMT activity.

¹ Supported by NIH Grant CA36679.

² This research comprised part of the dissertation requirements completed by C-L. C. for a Ph.D. degree awarded by the University of Nebraska Medical Center, Omaha, NE.

³ To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, 7650 Remsen, Hanover, NH 03755-3835.

Received 10/25/91. Accepted 1/24/92.

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