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Microsomal Metabolism of Nitrosoureas¹

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

N,N'-Bis(2-chloroethyl)-N-nitrosourea (BCNU) is a substrate for a microsomal enzyme of mouse liver. The reaction requires NADPH, and the product is 1,3-bis(2-chloroethyl)urea. This activity is also found in mouse lungs but not in several other tissues. With reaction conditions under which BCNU is not chemically degraded, the K_m for BCNU with liver microsomes is 1.7 mM; nicotine is a competitive inhibitor with a K_l of 0.6 mM. N-Methyl-N-nitrosourea is denitrosated in a similar reaction.

N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea and N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea are also substrates for microsomal enzymes, but the products of these reactions are ring-hydroxylated derivatives. The K_m value for N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea is 3.0 mM and that for N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl-N-nitrosourea is 1.0 mM. The hydroxylase activity is also present in lungs, but not in the other mouse tissues.

The rates of microsomal metabolism of BCNU, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea, and N-(2-chloroethyl - N' - (trans - 4 - methylcyclohexyl) - N - nitrosourea are fast enough to allow metabolism of large portions of administered doses before chemical decomposition of the drugs occurs.

¹ Presented in part at the Sixty-fifth Annual Meeting of the American Association for Cancer Research, March 1974. Supported by Contract N01CM-43784 with the Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education, and Welfare.

Received 8/ 2/74. Accepted 10/11/74.