NOICM-43784with the Divisionof Cancer Treatment, National Cancer

N,N'-Bis(2-chloroethyl)-N-nitrosourea (BCNU) is a sub strate for a microsomal enzyme of mouse liver. The reaction requires NADPH, and the product is 1,3-bis(2-chloro ethyl)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 Km for BCNU with liver microsomes is 1.7 mM; nicotine is a competitive inhibitor with a K1 of 0.6 [email protected] is denitrosated in a similar reaction. N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea and N(2chloroethyl)-N'-(trans-4-methylcyclohexyl)N-nitroso urea are also substrates for microsomal enzymes, but the products of these reactions are ring-hydroxylated deriva tives. The Km 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 I .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-(2chloroethyl)-N'-cyclohexyl-N-nitrosourea, and N-(2-chlo roethyl N' (trans 4 methylcyclohexyl) N nitro sourea are fast enough to allow metabolism oflarge portions of administered doses before chemical decomposition of the drugs occurs.