title: Structural requirements for the inhibition of human monocyte carboxylesterase by organophosphorus compounds.
abstract: Human blood monocyte carboxylesterase (CBE) is inhibited by a variety of organophosphorus compounds including arylphosphates and arylphosphites and some alkylphosphites. Triphenyl phosphate and triphenyl phosphite with Ki values of 8 x 10(-9) M and 4.8 x 10(-8) M, respectively, are the most potent inhibitors of this enzyme evaluated by this study. The arylphosphates vary in their capacity to inhibit carboxylesterase activity. Diphenyl phosphate with its strong negative charge is not a potent inhibitor (Ki = 1 x 10(-4) M), whereas if its negative charge is neutralized, as in diphenyl methyl phosphate, its capacity to inhibit carboxylesterase is significantly increased. Compounds with increased bulk, such as trinaphthyl phosphate, only inhibit the enzyme at concentrations of 10(-5) M or greater. Arylphosphites have inhibitory capacities similar to the arylphosphates. Alkylphosphites (tributyl phosphite/triethyl phosphite) inhibit carboxylesterase activity, whereas alkylphosphates (tributyl phosphate/triethyl phosphate) have no inhibitory effect. Arylphosphines and arylphosphine oxides do not inhibit carboxylesterase activity. This study demonstrates that organophosphates and organophosphites are relatively effective inhibitors of human monocyte CBE activity with the exception of the alkylphosphates which have no inhibitory activity. We conclude that molecular bulk and charge have a significant role in determining the potency of organophosphorus inhibitors of monocyte CBE. The observed variations in the degree of esterase inhibition by organophosphorus compounds as well as the differences in the pathological expression of neuropathic disorders associated with such chemicals suggest that different esterase enzymes derived from the family of esterase genes may mediate the different neuropathies observed with organophosphorus exposures. Such data also provide the rationale for the kinetic analyses of esterases and the design of non-toxic organophosphorus compounds with low or no monocyte CBE inhibitory capacity to reduce the potential of these commonly used chemicals for human toxicity.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: A M
authors.initials: AM
authors.lastname: Saboori
authors.forename: D M
authors.initials: DM
authors.lastname: Lang
authors.forename: D S
authors.initials: DS
authors.lastname: Newcombe
mesh_terms: D001665:Binding Sites; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D010755:Organophosphates; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D017905:Phosphites
chemical_list: D010755:Organophosphates; D009943:Organophosphorus Compounds; D017905:Phosphites; C013318:triphenyl phosphite; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; C005445:triphenyl phosphate