Inhibition of esterases

In addition to effects mediated through glucocorticoid secretion (stress-related), a hypothetical mechanism for direct immunotoxicity of organophosphates is the inhibition of esterases and stabilization of the lysosomal membrane of lymphocytes, thus blocking release of lymphokines (Sharma and Reddy 1987). 

Esterases of the Juvenile Hormone of Insects Many works have been dedicated to the inhibition of esterases of the juvenile hormone of insects. The purpose of these works is to control insect populations by ehminating their metamorphosis. Among the numerous trifluoromethyl ketones that have been synthesized, thioalkyl derivatives of trifluoroacetone have been shown to be the most active ones. Curiously, the corresponding alcohols are also excellent inhibitors. Trifluoromethyl ketones can also inhibit other insect esterases antenna esterases and esterases that are involved in the release of pheromones (Figure 7.33). The inhibition of these latter ones can also be interesting for insect control purposes. 

The inhibitory effect of profenofos on esterase activity towards I-naphthyl acetate in the crude homogenates after a 30 min incubation, is shown in Fig. 13-1-There was some inhibition of esterase activity in the susceptible and ail the resistant strains (-20%) however, there was no inhibition with J-naphthyl acetate in the partially purified resistant enzyme extract. Increasing the profenofos beyond a threshold concentration of 0.64 pmol L 1 did not have any additional effect. 

Nonspecific esterase activity of crude homogenate prepared from A. gossypii (clone 968E) after incubation with PBO is shown in Fig. 13,4, There was clear inhibition of esterase activity in these incubations over 40 minutes, and this inhibition increased with PBO concentration. However, the limited solubility of PBO precluded use of concentrations exceeding 2 mmol L... 

Figure 13.3. Effects of incubation time on PBO inhibition of esterase-mediated hydrolysis of I-naphthyl acetate in resistant and susceptible H. armtgera homogenates and a partially perilied enzyme from the resistant strain.

Figure 13.4. Effects of incubation lime and PBO concentration on PBO inhibition of esterase-mediated hydrolysis oi [ -naphthyl acetate in homogenates of A. OJ. v/m ...

In contrast, using crude homogenates prepared from M. persitme no inhibition of esterase activity was found over 40 minutes, even at concent rati ons of 2 mmol L 1 PBO (Fig. 13.5). 

There was a lack of inhibition of esterase activity observed in the //. urmiger-siiseeplible enzyme compared with that in the resistant enzyme, Also, no inhibition of the esterase (E4) was observed in M. persiste furthermore, inhibition... 

The apparent IC50 for test compounds differs between the cell lines, possibly reflecting species differences. However, ratios of ICjo values for NTE AChE show similar patterns >40 for m>n-OPIDN-inducing compounds (paraoxon and malaoxon) and those unlikely to cause OPfDN (chlorpyrifos-oxon, dichlorvos. and trichlorphon) low ratios (some <1) for the other compounds, all of which induce OPIDN. IC50 values for inhibition of esterases are lower than those for cytotoxicity. 

Various anticholinestera.scs are biologically potent chemicals that inhibit choIinesCera.scs via covalent interaction at the serine residue of the active site. Although enzyme inhibition may be reversible, there is the potential that other proteins may be modified and that several related enzymes may be inhibited. In many cases, it cannot be determined if the immunomodulatory effects are the result of inhibition of esterases or due to related mechanlsnis. 

The inhibition of carbonic anhydrase by anions has long been recognized. The inhibitory effect of Cl was noted by early investi-gators(19). A later study of anion inhibition by stopped-flow techniques was compromised by the presence of 80mM Cl in buffers used (20). The inhibition of the hydrase activity of the Cobalt(II) substituted enzyme has been investigated over the full pH range(21). Anionic inhibition of esterase activity has been studied by initial rate techniques(11-13) and by complexometric titration(22). None of the work thus far published has included full scale Michaelis-Menten analysis of the inhibition of the native Zinc(II) enzyme towards its natural substrate over an extended pH range. 

Estevez, J., Garcia-Perez, A., Barril, J., et al., 2004. The inhibition of the high sensitive peripherals nerve soluble esterases by Mipafox. A new mathematical processing for the kinetics of inhibition of esterases by organophosphorus compounds. Toxicol. Lett. 151, 243-249. 

A. R. Main, Affinity and posphorylation constants for the inhibition of esterases by organophosphates. Science, 1964, 144, 992-993. 

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