Sensitivity of blood-clotting factors and digestive enzymes to inhibition by organophosphorus pesticides

Abstract

Organophosphorus pesticide toxicology is normally evaluated in relation to inhibition of cholinesterases (acetyl and butyryl), neuropathy target esterase, and carboxylesterases, with less attention given to other physiologically important hydrolases. This study considers the relative organophosphate sensitivities of the aforementioned serine hydrolases compared with purified blood‐clotting factors (thrombin, plasmin, and kallikrein) and digestive enzymes (α‐chymotrypsin, trypsin, and elastase), assayed under similar conditions. Inhibitors that we examined are organophosphorus insecticides or their activated metabolites (paraoxon, chlorpyrifos oxon, and profenofos) and other toxicants (phenyl saligenin cyclic phosphonate and tribufos) for comparison with values that are found in the literature for the fluorophosphonates (isoflurophate and sarin). Thrombin is the most sensitive blood‐clotting factor with IC‐50 values of 19 to 160 μM for tribufos, the cyclic phosphonate, isoflurophate, and profenofos; plasmin and kallikrein are less affected (IC‐50 >100 μM). α‐Chymotrypsin, trypsin, and elastase are most sensitive to the cyclic phosphonate (IC‐50 1.3–15 μM) and less so to isoflurophate, sarin, and profenofos (IC‐50 values from 3.6 to greater than 100 μM). The cholinesterases, carboxylesterase, and neuropathy target esterase are the most sensitive to inhibition with IC‐50 values for the insecticides of less than 0.001 to 0.6, 0.002 to 0.009, and 0.15 to 100 μM, respectively. The generally low potency of these organophosphates for blood‐clotting factors and digestive enzymes suggests that associated toxic effects are unlikely at sublethal doses. © 1999 John Wiley & Sons, Inc. J Biochem Toxicol 14: 51–56, 2000

Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon

“…This difference in potency is likely due to the greater reactivity of paraoxon with the enzymes as the fold difference in IC 50 values was almost identical to the reciprocal of the fold difference in the bimolecular rate constants for the enzyme-oxon pairs for which bimolecular rate constants could be determined (Table 2). Previous reported values for the IC 50 of chlorpyrifos oxon and paraoxon for the inhibition of porcine liver carboxylesterase were 2 and 3 nM, respectively (Quistad and Casida, 2000). These values are approximately one order of magnitude larger than the corresponding values we determined for CES1, which is the carboxylesterase present in the largest amount in human liver.…”

“…This suggests that CES1 is more sensitive to inhibition by chlorpyrifos oxon and paraoxon than are porcine carboxylesterases. However, we do note that our incubations of enzyme and oxon were done at 37°C versus the 25°C used by Quistad and Casida (2000), which may account for some of the differences observed.…”

Identifying safer anti-wear triaryl phosphate additives for jet engine lubricants

“…Consistent with the CES inhibition by TAPs in this study (Figs. 4C,D,F, Table 2), Quistad and Casida reported the high sensitivity of CES to CBDP inhibition [24]. APH, reported to be involved in cognition [48, 49], was inhibited in vivo by TAP metabolite (s) (Fig.…”

“…The in vitro role of microsomes in the metabolism of TAPs, including T o CP, was established by Sprague and Castles in 1985 [22]. An analogue of CBDP, phenyl saligenin phosphate [23], is a potent inhibitor of neuropathy target esterase (NTE) [24], the inhibition and aging of which results in organophosphate (OP)-induced delayed neuropathy (OPIDN) [25]. Toxic metabolites of other jet engine TAP additives, including those evaluated in this study, have not yet been described in the literature.…”

Mass Spectrometric Analyses of Organophosphate Insecticide Oxon Protein Adducts

“…The involvement of OPs at individual ACh receptors (nAChR, mAChR) and noncholinergic protein targets has been reported with increasing frequency (Albuquerque et al 1988; Bomser and Casida 2001; Corrigan et al 1994; Ehrich et al 1994; Eldefrawi and Eldefrawi 1983; Huff et al 1994; Katz and Marquis 1992; Li et al 2000a, 2000b; Pala et al 1991; Quistad and Casida 2000; Quistad et al 2000, 2001; Richards et al 1999; Schuh et al 2002; van den Beukel et al 1998; Ward et al 1993; Ward and Mundy 1996). However, only a few investigations have identified OP-altered protein targets, despite the clear evidence suggesting involvement in toxic mechanisms.…”