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Metabolism of O⁶-Benzylguanine, an Inactivator of O⁶-Alkylguanine-DNA Alkyltransferase¹

Division of Hematology-Oncology, The University of Chicago, Chicago, Illinois 60637 [M. E. D., J. H. M.]; Carcinogen-Modified Nucleic Acid Chemistry, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [M-Y. C., R. C. M.]; Departments of Cellular and Molecular Physiology and of Pharmacology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]; and Departments of Pediatrics and Pathology and the Preuss Laboratory for Brain Tumor Research, Duke University Medical Center, Durham, North Carolina [H. S. F.]

O⁶-Benzylguanine effectively inactivates the DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase, leading to an increase in the therapeutic index of 1,3-bis(2-chloroethyl)-1-nitrosourea in nude mouse xenograft studies. To investigate the fate of this inactivator in mammalian systems, we examined its biodistribution and metabolism following i.p. administration of 8-[³H]-O⁶-benzylguanine to male Sprague-Dawley rats and BALB/c mice. Following administration to rats, there were significantly higher levels of radioactivity in liver than in lung, spleen, kidney, small intestine, and esophagus for up to 24 h. Major urinary metabolites were identified as O⁶-benzyl-7,8-dihydro-8-oxoguanine, N²-acetyl-O⁶-benzylguanine, and N²-acetyl-O⁶-benzyl-7,8-dihydro-8-oxoguanine. Debenzylated metabolites included guanine, 7,8-dihydro-8-oxoguanine, and N²-acetylguanine. In contrast to rat metabolism, acetylated derivatives were not found in mouse urine. However, O⁶-benzyl-7,8-dihydro-8-oxoguanine was a major metabolite in the mouse. O⁶-Benzyl-7,8-dihydro-8-oxoguanine was a very effective O⁶-alkylguanine-DNA alkyltransferase inactivator and exhibited a 50% effective dose in HT29 cell extracts of 0.3 µM compared to 0.2 µM for O⁶-benzylguanine. The O⁶-alkylguanine-DNA alkyltransferase depleting activity of N²-acetyl-O⁶-benzylguanine and N²-acetyl-O⁶-benzyl-7,8-dihydro-8-oxoguanine were, respectively, 120- and 325-fold lower than O⁶-benzylguanine in HT29 cell-free extracts.

¹ This work has been supported in part by the National Cancer Institute through Grants CA47228 (M. E. D.), CA57725 (A. E. P., M. E. D., H. S. F.), CA-18137 (A. E. P.), NCI Contract NO1-CO-74101 with ABL (M-Y. C., R. C. M.), and by NINDS through Grants NS30245 (H. S. F.) and NS20023 (H. S. F.) and ACS DHP-67E (H. S. F.).

² To whom requests for reprints should be addressed.

Received 2/23/94. Accepted 8/ 2/94.

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