Inhibition of Xenobiotic-Degrading Hydrolases by Organophosphinates
Abstract
An abridged synthesis of 4-nitrophenyl diphenylphosphinate is described in which this compound was prepared in two steps. Chromatographic characteristics of four series of 4-nitrophenyl organophosphinates are described including results on normal-phase, reversed-phase and chiral-phase columns. Enantiomers of four organophosphinates were separated on a commercial (R)-N-(3, 5-dinitrobenzoyl)phenylglycine chiral-phase column. Analysis of 4-nitrophenyl diphenylphosphinate was performed after administration to mice and after incubation with rabbit serum. Porcine liver carboxylester hydrolase (carboxylesterase) was rapidly inhibited by 4-nitrophenyl organophosphinates containing aryl or heteroaryl groups directly bound to phosphorus. The most potent inhibitor was 4-nitrophenyl di-2-thienylphosphinate. Concentration of CARBOXYL- CARBON 14 procaine in blood on mice were increased three-fold for 27 min by exposure to 0-4-nitrophenyl diphenylphosphinate 2 h prior to CARBOXYL- CARBON 14 procaine injection ip. The substrate specificity of arylester hydrolase partially purified from rabbit serum was studied. Acetylcholinesterases from electric eel and from bovine erythrocytes were inhibited stereoselectively by P(=)4-nitrophenyl ethyl (phenyl) (EPP) and P(=) 4-nitrophenyl isopropyl (phenyl)phosphinate (IPP). Phosphorylase kinase from rabbit muscle appeared to have catalytic activity toward EPP. Keywords: Enzyme inhibitors, Organophosphinate pretreatment agents, Enzyme reactivation, Drug interaction, Stereoselectivity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1986
- Accession Number
- ADA202378
Entities
People
- Gregory T. Payne
- James M. Joly
- John R. Grothusen
- P. K. Bryson
- Thomas M. Brown
Organizations
- Clemson University