Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs

Int J Mol Sci. 2013 Dec 18;14(12):24692-705. doi: 10.3390/ijms141224692.

Abstract

The metabolism of amine-containing drugs by cytochrome P450 enzymes (P450s) is prone to form a nitrosoalkane metabolic intermediate (MI), which subsequently coordinates to the heme iron of a P450, to produce a metabolic-intermediate complex (MIC). This type of P450 inhibition, referred to as mechanism-based inactivation (MBI), presents a serious concern in drug discovery processes. We applied density functional theory (DFT) to the reaction between N-methylhydroxylamine (NMH) and the compound I reactive species of P450, in an effort to elucidate the mechanism of the putative final step of the MI formation in the alkylamine metabolism. Our DFT calculations show that H-abstraction from the hydroxyl group of NMH is the most favorable pathway via which the nitrosoalkane intermediate is produced spontaneously. H-abstraction from the N-H bond was slightly less favorable. In contrast, N-oxidation and H-abstraction from the C-H bond of the methyl group had much higher energy barriers. Hence, if the conversion of NMH to nitrosoalkane is catalyzed by a P450, the reaction should proceed preferentially via H-abstraction, either from the O-H bond or from the N-H bond. Our theoretical analysis of the interaction between the MI and pentacoordinate heme moieties provided further insights into the coordination bond in the MIC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkanes / chemistry
  • Alkanes / metabolism*
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / metabolism
  • Cytochrome P-450 Enzyme System / metabolism*
  • Hydrogen / chemistry
  • Hydroxylamines / chemistry
  • Hydroxylamines / metabolism*
  • Models, Molecular
  • Thermodynamics

Substances

  • Alkanes
  • Calcium Channel Blockers
  • Hydroxylamines
  • Hydrogen
  • Cytochrome P-450 Enzyme System
  • N-methylhydroxylamine