Microsomal metabolism of nitrosoureas
Hill, D.L.; Kirk, M.C.; Struck, R.F.
Cancer Research 35(2): 296-301
1975
ISSN/ISBN: 0008-5472 PMID: 234031 Document Number: 92084
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 Km for BCNU with liver microsomes is 1.7 mM; nicotine is a competitive inhibitor with a Ki of 0.6 mM. N-Methyl-N-nitrosourea is denitrosated in a similar reaction. N- (2-Chloroetyhy)- 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 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 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-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.