J. Hilton, M. Walker
Dec 1, 1975
Citations
0
Influential Citations
29
Citations
Quality indicators
Journal
Biochemical pharmacology
Abstract
Abstract Rat liver microsomal mixed function oxidase catalyzes the hydroxylation of the cyclohexyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) to give at least five metabolites. When exposed to alkaline pH at 100° CCNU and its metabolites quantitatively release their cyclohexyl moiety as cyclohexylamine and aminocyclohexanol respectively. The N -(2,4-dinitrophenyl) derivatives of cyclohexylamine and aminocyclohexanols were separated by high pressure liquid chromatography. The metabolites in vitro and in vivo have been identified as trans -2-hydroxy CCNU, cis -3-hydroxy CCNU, trans -3-hydroxy CCNU, cis -4-hydroxy CCNU and trans -4-hydroxy CCNU. Ring hydroxylation axial to the 1-(2-chloroethyl)-1-nitrosourea group ( cis -2-, trans -3-, cis -4-) is favored over equatorial attack ( trans -2-, cis -3-, trans -4-). Pretreatment of rats with phenobarbital leads to an increased rate of hydroxylation and a change in the relative amounts of the hydroxylated products. The significance of hydroxylation in relation to the antitumor activity of CCNU is discussed.