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Enzyme-alterable Alkylating Agents

IX. The Enzymatic Transformation of Some Nitrogen Mustards in the Presence of Carbon Dioxide: Implications in Respiration¹

The Chemical Research Division, Chemical Research and Development Laboratories, Edgewood Arsenal, Maryland, and Department of Surgery, Sinai Hospital of Baltimore, Inc., and The Johns Hopkins University School of Medicine, Baltimore, Maryland

In vitro kinetic studies in various biologic media have led to the observation of an enzyme in blood serum that catalyzes the reaction between secondary nitrogen mustards and carbon dioxide to form substituted oxazolidinones.

This reaction causes the very rapid degradation of certain nitrogen mustards frequently employed in cancer chemotherapy. Upon contact with blood or animal tissues, agents such as degranol and nor-HN2 are immediately transformed into products incapable of undergoing typical alkylation reactions. In light of these observations reevaluation of pharmacologic data thus far collected on these nitrogen mustards is indicated.

Interpretation of the kinetic data obtained indicates that the enzyme catalyzes carbamate formation—a reaction of importance for the transport of carbon dioxide in blood. R₂NH + CO₂ R₂NCOO + H It is proposed that a normal metabolic function of this enzyme is to catalyze this reaction during respiration.

¹ Supported in part by the U.S. Army Edgewood Arsenal Chemical Research and Development Laboratories In-House Laboratory Independent Research Program and in part by a research grant (CA 02478) from the National Cancer Institute, USPHS, Bethesda, Maryland.

Received 6/21/65.