title: In vitro effects of organophosphorus compounds on calmodulin activity.
abstract: In vitro effects of organophosphorus compounds (OP), such as malathion (M), methyl parathion (MP) and ethyl parathion (EP), on calmodulin (CaM) activity and its active conformation were studied to understand the mechanism(s) of neurotoxicity, since CaM is known to regulate Ca2+ transport and the enzymes involved in signal transduction and nucleotide metabolism. The biological activity of CaM was assessed as a measure of phosphodiesterase (PDE) stimulation. The effect of OP compounds on the active conformation of CaM was determined by studying the binding of fluorescence probes, namely N-phenyl-1-naphthylamine (NPN), and changes in dansyl-calmodulin fluorescence. Dansylated calmodulin was also used to study the effect of OP compounds on complex formation between CaM and PDE. All three OP compounds inhibited the CaM activity and its active conformation in a concentration-dependent manner. Malathion was less effective in comparison to EP and MP, with IC50 values of 37 microM, 34.5 microM and 32 microM, respectively, for CaM activity. EP and MP significantly altered NPN and dansyl-calmodulin fluorescence (50 microM concentrations of OP compounds), whereas M did not show any significant effect on NPN fluorescence. All these compounds significantly affected complex formation between the dansylated CaM and PDE. These results suggest that OP compounds may be interacting with CaM, altering its active conformation, and thus may be inhibiting its biological activity.
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, Jackson 39216.
authors.forename: I
authors.initials: I
authors.lastname: Pala
authors.forename: P J
authors.initials: PJ
authors.lastname: Vig
authors.forename: D
authors.initials: D
authors.lastname: Desaiah
authors.forename: A
authors.initials: A
authors.lastname: Srinivasan
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008294:Malathion / Q000633:toxicity*; D008743:Methyl Parathion / Q000633:toxicity*; D010278:Parathion / Q000633:toxicity*; D011487:Protein Conformation
chemical_list: D002147:Calmodulin; D008743:Methyl Parathion; D010278:Parathion; D002118:Calcium; D008294:Malathion