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In Vitro Hepatotoxicity of SR 4233 (3-Amino-1,2,4-benzotriazine-1,4-dioxide), a Hypoxic Cytotoxin and Potential Antitumor Agent¹

Departments of Anesthesia [A. K. C., J. R. T.] and Radiation Oncology [J. M. B.], Stanford University School of Medicine, Stanford, California 94305-5117, and Department of Radiation Oncology [M. A. B.], University of Pennsylvania School of Medicine, Philadelphia, PA 19104-3357

SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is presently undergoing investigation as an antitumor agent because of its high selective toxicity for hypoxic cells in vitro and in vivo. It has been found to be 15 to 200 times more toxic to hypoxic rodent and human cell lines than their normoxic counterparts. We investigated the toxicity of SR 4233 in primary cultures of hepatocytes under various oxygen tensions, ranging from 1% to 20% oxygen. The 50% lethal dose of SR 4233 was found to be 50 times lower in hepatocyte monolayers at 1% O₂ versus 20% O₂. Even at 4% O₂, a concentration that prevails in the pericentral area of the liver under conditions of normal blood flow, SR 4233 was an order of magnitude more toxic than at 20% O₂. All samples were analyzed for metabolites, and metabolism was found to be dependent on both the SR 4233 concentration and the oxygen tension. Formation of the major metabolite SR 4317 occurred to the greatest extent at the lowest oxygen concentration and the highest SR 4233 concentration. Very little metabolism occurred at 10 to 20% O₂, which is in agreement with data in Chinese hamster ovary cells under aerobic conditions.

¹ Supported by National Institute of Occupational Safety and Health Grants OH 00978 (J. R. T., A. K. C.) and CA 15201 (M. A. B., J. M. B.).

² To whom requests for reprints should be addressed.

Received 6/14/88. Revised 10/11/88. Revised 11/15/88. Accepted 11/17/88.