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Peroxidase-catalyzed Metabolism of Etoposide (VP-16-213) and Covalent Binding of Reactive Intermediates to Cellular Macromolecules¹

Clinical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892 [N. H., B. K. S.]; Division of Clinical Pharmacology, USPHS, Bethesda, Maryland [N. H.]; and Chemical Synthesis and Analysis Laboratories, Program Resources, Inc., National Cancer Institute-Frederick Cancer Research Facility, Frederick, Maryland [J. N., J. R.]

The horseradish peroxidase- and prostaglandin synthetase-catalyzed oxidative metabolism of the highly active anticancer drug, etoposide (VP-16-213), has been studied in vitro. This oxidation of VP-16 resulted in the formation of VP-16 quinone, an aromatic VP-16 derivative and the corresponding aromatic VP-16 quinone. This oxidative metabolism of VP-16 also resulted in the formation of reactive species that covalently bound to exogenously added DNA and heat-inactivated microsomal proteins. The peroxidase-catalyzed binding was time dependent and required the presence of cofactors (hydrogen peroxide or arachidonic acid). The prostaglandin synthetase/arachidonic acid-catalyzed metabolism and binding of VP-16 were inhibited by indomethacin, an inhibitor of the cyclooxygenase, and were shown to involve the peroxidative arm of prostaglandin synthetase. Our studies show that the protein covalent binding species were formed as a result of O-demethylation of the drug as shown by the loss of specifically labeled (O-¹⁴CH₃) radioactivity from O-methoxy group and by incubating proteins with VP-16 quinones. In contrast, the covalent binding intermediates for DNA appeared to be different and VP-16-derived quinone methides are suggested as DNA binding species. Co-oxidation of VP-16 and the related drug, VM-26, during prostaglandin biosynthesis may be an important pathway for the metabolism of these agents and may play a role in their cytotoxic properties.

¹ Sponsored, at least in part, by the National Cancer Institute, Department of Health and Human Services, under Contract N-01-23910 with Program Resources, Inc. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of the trade names, commercial products, or organizations imply endorsement by the US government.

² Present address: Department of Oncology, Soroka Medical Center, Beer-Sheba, 84101, Israel.

³ To whom requests for reprints should be addressed, at Bldg. 10, Room 6N-119, National Cancer Institute, NIH, Bethesda, MD 20982.

Received 5/14/87. Revised 8/ 6/87. Accepted 8/11/87.

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