Reactivation of carboxylester hydrolase following inhibition by 4-nitrophenyl organophosphinates.
Porcine liver carboxylester hydrolase (EC 3.1.1.1; 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 for which the median inhibitory concentration was 7.4 X 10(-9) M. Rabbit liver monomeric carboxylester hydrolase was inhibited, separated from excess inhibitor by gel permeation chromatography, and observed for spontaneous or 1,1'-trimethylene-bis(4-formylpyridinium bromide) dioxime (TMB-4)-induced reactivation. Recovery was most rapid (k = 4 to 7 X 10(-4) min-1) from phosphinyl groups containing one alkyl substituent smaller than isopropyl and one aryl or heteroaryl group smaller than naphthyl. The di-2-thienylphosphinylated enzyme was an exception since it recovered rapidly while lacking an alkyl substituent. Oxime reactivation by TMB-4 doubled rates of recovery.
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004793:Enzyme Reactivators / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D004793:Enzyme Reactivators; D010721:Phosphinic Acids; D002265:Carboxylic Ester Hydrolases