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Microsomal Metabolism of Triazenylimidazoles¹

Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205

The antitumor agents 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide (DIC) and 5-[3,3-bis(2-chloroethyl)-1-triazenyl]imidazole-4-carboxamide (BIC) are substrates for NADPH-requiring microsomal enzymes of mouse liver. The products of DIC oxidation are 5-aminoimidazole-4-carboxamide (AIC) and formaldehyde. Those for BIC are AIC and, presumably, 2-chloroacetaldehyde. For DIC, the reaction has a pH optimum of 9.0; and the Michaelis constant (K_m) is 0.25 mM. At lower pH values, the K_m is not greatly increased; but there is a sharp rise in the K_m values above pH 9.0. For the enzyme-catalyzed production of AIC from BIC, the pH optimum is 7.5; the K_m value for BIC is 0.47 mM.

Of a variety of tissues tested for enzymatic activity, only liver accomplishes the conversion of DIC and BIC to AIC. Most of the activity in the liver is located in the microsomal fraction, although detectable activity is present in washed mitochondria. For liver microsomes, the rate of reaction for BIC is greater than that for DIC, but apparently neither rate is fast enough to allow extensive metabolism of large doses of these agents.

¹ A portion of this work was published as part of the Proceedings of the American Association for Cancer Research, May 1975. The investigation was supported by Contract NO1-CM-43784 with the Division of Cancer Treatment, National Cancer Institute, NIH, HEW.

Received 6/11/75. Accepted 8/ 8/75.

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