INACTIVATION OF CYTOCHROME P-450 ENZYMES BY CYCLOPROPYLAMINES

Abstract

Publisher Summary This chapter presents the results of a study conducted to analyze the inactivation of cytochrome P-450 enzymes by cyclopropylamines. The cyclopropyl moiety is a chemically novel entity possessing an electronic structure intermediate between that of alkyl and aryl systems. Cyclopropyl compounds also exhibit novel pharmacological properties in the inhibition of MAO. In this study, a series of p-substituted benzylcyclopropylamines was synthesized to examine the dependence of inhibition on the Hammett σ parameter and other physico–chemical indices. The corresponding N-isopropyl compounds were synthesized to act as reference controls. It was found that inactivation of P-450 increased with incubation time for cyclopropylamines. Experiments indicated that the time-dependent inactivation process required NADPH and was blocked by CO. The compounds had no effect on the NADPH generating system or NADPH-cytochrome P-450 reductase, and inactivation could not be blocked by glutathione or semicarbazide. Preliminary studies indicate that N-benzylcyclopropylamine tritiated at the benzylic position becomes covalently bound to microsomes in vitro. All of these results also suggest that the cyclopropylamines are suicide substrates for cytochromes P-450.