nitrophenols and diethyl-succinate

A series of substituted trifluoroketones were tested as inhibitors of mammalian liver microsomal carboxylesterase(s) hydrolyzing a variety of substrates including malathion, diethylsuccinate (DES) and p-nitrophenyl acetate (p-NpAc). The trifluoroketones used were very potent "transition state" inhibitors of crude mouse and human liver microsomal carboxylesterases as well as commercial porcine liver carboxylesterase (Sigma EC 3.1.1.1 Type I). These enzymes were found to differ in their sensitivity to the inhibitors employed, and some compounds caused dramatic activation of the hydrolysis of DES. In some but not all cases, a thioether beta to the carbonyl increased the inhibitory potency of the compound. Structure-activity relationships also were evaluated among aliphatic versus substituted and unsubstituted aromatic trifluoroketones. Kinetic parameters [i.e. Km, Vmax and (T1/2)e] for the mouse liver microsomes and the porcine carboxylesterase hydrolyzing DES were determined. Apparent high- and low-affinity forms were observed with each preparation. 3-Nonylthio-1,1,1-trifluoropropan-2-one was synthesized by the reaction of the corresponding thiol with 3-bromo-1,1,1-trifluoroacetone, and apparent synergism was observed when it was coadministered i.p. with malathion to mice.

Topics: Animals; Carboxylic Ester Hydrolases; Ketones; Kinetics; Malathion; Mice; Microsomes, Liver; Nitrophenols; Species Specificity; Structure-Activity Relationship; Succinates; Swine

Treatment with 0.5% (w/w) dietary clofibrate, a peroxisome proliferator, for 14 days induced microsomal carboxylesterase activities for five substrates including malathion, clofibrate, diethylsuccinate, diethylphthalate, and p-nitrophenylacetate in liver and kidney of male Swiss-Webster mice and Sprague-Dawley rats. The induction was substrate, tissue, and species dependent. The carboxylesterase activity was induced in mouse from 1.2- to 2.2-fold (liver) and from 1.1- to 1.7-fold (kidney) depending upon substrate used. Analogous values from rat ranged from 1.0- to 1.4-fold (liver) and from 1.1- to 1.8-fold (kidney). Enzyme activities were either decreased or not affected in testes of treated mice and rats. Substituted trifluoroketones ("transition-state" inhibitors of carboxylesterase) were found to be very potent inhibitors of clofibrate-metabolizing carboxylesterase(s) and to be potentially useful in distinguishing among isozymes. The inhibition data suggested that changes in carboxylesterase activity following clofibrate treatment were both qualitative and quantitative.

Topics: Animals; Carboxylic Ester Hydrolases; Clofibrate; Enzyme Induction; Kidney; Malathion; Male; Mice; Microsomes; Microsomes, Liver; Nitrophenols; Phthalic Acids; Rats; Rats, Inbred Strains; Succinates; Testis