ToxSci Advance Access originally published online on January 31, 2006
Toxicological Sciences 2006 91(1):166-172; doi:10.1093/toxsci/kfj124
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Each Lipase Has a Unique Sensitivity Profile for Organophosphorus Inhibitors
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720–3112, USA
1 To whom correspondence should be addressed at Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720–3112. Fax: (510) 642-6497. E-mail: ectl{at}nature.berkeley.edu.
Received December 21, 2005; accepted January 27, 2006
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ABSTRACT |
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Lipases sensitive to organophosphorus (OP) inhibitors play critical roles in cell regulation, nutrition, and disease, but little is known on the toxicological aspects in mammals. To help fill this gap, six lipases or lipase-like proteins are assayed for OP sensitivity in vitro under standard conditions (25°C, 15 min incubation). Postheparin serum lipase, lipoprotein lipase (LPL) (two sources), pancreatic lipase, monoacylglycerol (MAG) lipase, cholesterol esterase, and KIAA1363 are considered with 32 OP pesticides and related compounds. Postheparin lipolytic activity in rat serum is inhibited by 14 OPs, including chlorpyrifos oxon (IC50 50–97 nM). LPL (bovine milk and Pseudomonas) generally is less inhibited by the insecticides or activated oxons, but the milk enzyme is very sensitive to six fluorophosphonates and benzodioxaphosphorin oxides (IC50 7–20 nM). Porcine pancreatic lipase is very sensitive to dioctyl 4-nitrophenyl phosphate (IC50 8 nM), MAG lipase of mouse brain to O-4-nitrophenyl methyldodecylphosphinate (IC50 0.6 nM), and cholesterol esterase (bovine pancreas) to all of the classes of OPs tested (IC50 < 10 nM for 17 compounds). KIAA1363 is sensitive to numerous OPs, including two O-4-nitrophenyl compounds (IC50 3–4 nM). In an overview, inhibition of 28 serine hydrolases (including lipases) by eight OPs (chlorpyrifos oxon, diazoxon, paraoxon, dichlorvos, and four nonpesticides) showed that brain acetylcholinesterase is usually less sensitive than butyrylcholinesterase, liver esterase, cholesterol esterase, and KIAA1363. In general, each lipase (like each serine hydrolase) has a different spectrum of OP sensitivity, and individual OPs have unique ranking of potency for inhibition of serine hydrolases.
Key Words: chlorpyrifos oxon; cholesterol esterase; lipase; lipoprotein; organophosphorus.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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Organophosphorus (OP) toxicology research has evolved from evaluating acetylcholinesterase (AChE) inhibition (the primary effect) to consideration of multiple secondary targets. There are several hundred serine hydrolases, including lipases, in humans. Although at least 50 are known to be OP targets, only about 20 have been systematically evaluated for OP sensitivity and relevance, leading to AChE, neuropathy target esterase-lysophospholipase (NTE-LysoPLA), butyrylcholinesterase (BChE), platelet-activating factor acetyl hydrolase (PAF-AH), monoacylglycerol (MAG) lipase, fatty acid amide hydrolase (FAAH), and carboxylesterase as most important to mammalian toxicology (Casida and Quistad, 2004
, 2005; Quistad et al., 2006).
Lipases are serine hydrolases which cleave lipids essential as energy sources (e.g., triacylglycerols) and signaling molecules (e.g., 2-arachidonoylglycerol) (Dinh et al., 2002; Wong and Schotz, 2002). Lipoprotein lipase (LPL, EC 3.1.1.34
[EC]
) and hepatic triglyceride lipase (H-TGL, EC 3.1.1.3
[EC]
) are the major lipolytic enzymes for metabolism of lipoproteins in circulation (Jackson and McLean, 1991). These enzymes, which play key roles in lipid metabolism and transport, are anchored to the plasma membrane of endothelial cells and are released after intravenous heparin administration—thus the term postheparin plasma lipolytic activity (Mead et al., 2002). The major tissue sources of LPL are adipose and muscle, while H-TGL is synthesized by hepatocytes. Bovine milk is a major source of LPL (Bengtsson-Olivecrona and Olivecrona, 1991) and related LPLs have been isolated from Pseudomonas (Sugiura et al., 1977). Human, rat, and bovine LPL have 447–450 amino acids and are highly homologous to each other. Human LPL is 47% homologous to human H-TGL (Jackson and McLean, 1991; Raisonnier et al., 1995) and 28% homologous to porcine pancreatic lipase (EC 3.1.1.3
[EC]
) (Wion et al., 1987), a key enzyme of dietary triacylglycerol uptake (Hadváry et al., 1988). Amino acid sequences near the active site serine are very similar for each of these mammalian lipases (Jackson and McLean, 1991; Raisonnier et al., 1995). MAG lipase modulates the pharmacological activity of 2-arachidonoylglycerol, the principal natural ligand acting at the CB1 cannabinoid receptor (Sugiura and Waku, 2000). Rat brain MAG lipase (EC 3.1.1.23
[EC]
) is a 33-kDa protein and is unique among lipases by using only monoacylglycerols as substrates (Dinh et al., 2002; Karlsson et al., 2000). Cholesterol esterase (EC 3.1.1.13
[EC]
) is synthesized in the pancreas and transported into the intestine, where it catalyzes fat and vitamin absorption; this 74-kDa enzyme from porcine pancreas is quite different from other lipases (DiPersio et al., 1990). KIAA1363 is a serine hydrolase with lipase homology, associated with cancer cell invasiveness (Jessani et al., 2002) and is the principal enzyme in mouse brain for detoxifying low levels of chlorpyrifos oxon (CPO), the active metabolite from the major insecticide chlorpyrifos (Nomura et al., 2005).
Inhibition of lipase activity could disrupt lipid homeostasis, thereby causing pathological conditions in mammals. For example, cardiac-specific gene knockout of LPL leads to defective triacylglycerol metabolism in plasma (Augustus et al., 2004). OP compounds in general, and pesticides in particular, are potential inhibitors of lipases, but a systematic investigation of OP potency and selectivity is lacking. This investigation partially fills the gap by determining the sensitivity and structure-activity relationships (SAR) for 32 OP compounds inhibiting six lipases, lipoprotein lipases, or lipase-like enzymes.
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MATERIALS AND METHODS |
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Enzymes and chemicals.
Swiss-Webster mouse brains were from Pel-Freez (Rogers, AR). The following purified enzymes and substrates were from Sigma (St. Louis, MO): LPL (bovine milk, Pseudomonas), pancreatic lipase (porcine), unpurified plasma for BChE (mouse), liver esterase (a carboxylesterase) (porcine), cholesterol esterase (bovine pancreas), urokinase-type plasminogen activator (human urine), 4-nitrophenyl butyrate, palmitoyl CoA, and pGlu-Gly-Arg-p-nitroanilide. 14C-Mono- and 14C-triolein were synthesized from 14C-oleic acid (PerkinElmer Life Sciences, Boston, MA). 3-Mercaptopropane-1,2-diol tributyrate (O,O,S-tributyrin; O,O,S-TB) was made from 3-mercaptopropane-1,2-diol and butyric acid anhydride.
Enzymes studied and assays used.
Table 1 summarizes the enzyme sources and assays. The test conditions in every case gave linearity of product formation with enzyme level and time. In this investigation, candidate inhibitors were added in dimethyl sulfoxide (DMSO) (5 µl), and the mixture was incubated for 15 min before adding the substrate to determine activity. Assays were conducted at 25°C for comparison to previous data from this laboratory. Appropriate controls were included for the DMSO vehicle. Tributyrin was used as a convenient substrate for early studies with lipases (Aldridge and Reiner, 1972). Subsequently, O,O,S-TB was even more useful since it allowed colorimetric assay of pancreatic lipase activity (Kurooka et al., 1976).
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Postheparin serum lipolytic activity assay.
Sprague-Dawley rats (ca. 220 g) were treated iv with heparin (0.25 ml of a 1 mg/ml solution in 145 mM NaCl) and blood withdrawn after 5 min (Fielding, 1969
). Postheparin rat serum (10 µl) was added to 100 mM Tris (pH 8.8, 25°C) (185 µl). After the inhibition reaction, 5,5'-dithiobis(2-nitrobenzoic acid) (50 µl, 1.76 mg/ml) and O,O,S-TB (50 µl, 0.15 mg/ml emulsion in 100 mM Tris, pH 7.7, 25°C) were added, with kinetic assay at 412 nm for 15 min at 25°C using a microplate reader with 96-well plates (Versamax, Molecular Devices, Sunnyvale, CA). For comparison, 14C-triolein was examined as a possibly equivalent substrate. Postheparin rat serum (10 µl) was added to 100 mM Tris (pH 8.8, 25°C) (185 µl) containing 3 µM lecithin and 0.01% Triton X-100 in 4-ml glass vials. Following the inhibition reaction, 14C-triolein (38 µM final concentration, 50,000 dpm) was added in DMSO (5 µl). After vortexing for 10 s, samples were incubated 1 h at 25°C. The reaction was stopped by addition of chloroform:methanol:hexane, 1.25:1.4:1 (2.5 ml) and 200 mM K2CO3 (0.83 ml). Vials were capped, mixed, centrifuged, and potassium 14C-oleate was extracted into the upper aqueous phase, 1.5 ml of which was quantified by liquid scintillation counting. Under these conditions control preparations hydrolyze 2% of the 14C-triolein.
Other lipase assays.
Lipoprotein and pancreatic lipase activities were determined as described for postheparin serum, but using LPL (bovine milk and Pseudomonas) and porcine pancreatic lipase (2, 6 and 50 units per well, respectively). MAG lipase activity was monitored as release of 14C-oleic acid from 1(3)-14C-oleoyl-monoolein using mouse brain homogenate (Quistad et al., 2006). Cholesterol esterase activity was determined as described, with 4-nitrophenyl butyrate as substrate (no addition of taurocholate) (DiPersio et al., 1990). As validation of this colorimetric method, similar IC50 values are obtained for CPO, ethyl octylphosphonofluoridate (EOPF), and isopropyl dodecylphosphonofluoridate (IDFP) using cholesteryl 14C-oleate and taurocholate (data not shown) (DiPersio et al., 1990). KIAA1363 was assayed as 3H-CPO binding in mouse brain membranes as described (Nomura et al., 2005).
Other serine hydrolase assays.
Inhibition by eight OPs was compared for 28 serine hydrolases (including lipases) under similar conditions (15-min inhibition, 25°C). For comparisons of potency in vitro, some of the data used are from previous publications of this laboratory. Missing IC50 values were obtained by the same methods: AChE, mouse brain (Quistad et al., 2005b); BChE, mouse plasma (Quistad et al., 2005b); liver esterase (Est-L), porcine, using 4-nitrophenyl butyrate as substrate (Quistad and Casida, 2000); brain esterase (Est-B), mouse, using the 1200 x g supernatant of a 20% w/v homogenate in 100 mM phosphate, pH 7.4 and 4-nitrophenyl butyrate (as above); long-chain acyl-CoA hydrolase, mouse brain homogenate as for Est-B and palmitoyl-CoA as substrate (Yamada et al., 1996); urokinase-type plasminogen activator (u-PA), from human urine with p-Glu-Gly-Arg-p-nitroanilide as substrate (Liu and Gurewich, 1995).
Analysis of data.
The concentration of compound inhibiting 50% of enzyme activity (IC50) was derived with two to three levels (above and below the IC50, each in at least triplicate) in the range of 15–85% enzyme inhibition. Results are reported as the mean ± SD of the individual IC50 values for each OP (n = 3–6).
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RESULTS |
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Sensitivity Profiles
Candidate inhibitors are compared on the basis of SAR and potency.
IC50
200 nM (potent); 200 nM–10 µM (moderate); >10 µM (weak).
Postheparin Serum Lipolytic Activity
Assays with O,O,S-tributyrin.
Postheparin lipolytic activity in rat serum can be measured with either O,O,S-TB or 14C-triolein, which give similar IC50 values for CPO (80 ± 13 and 112 ± 41 nM, respectively). O,O,S-TB is used routinely in this investigation because of the ease of colorimetric assay. The lipolytic activity in rat serum increases 57% 5 min after iv treatment with heparin, and this postheparin lipolytic activity predominantly is from lipase(s) and not BChE, since the BChE-specific inhibitor ethephon (Haux et al., 2000) at 300 µM reduces hydrolysis only 10% for O,O,S-TB versus 90% for butyrylthiocholine (Supplementary Table 1). A related inhibition study with ethephon showed that O,O,S-TB is not a suitable substrate for lipase activity in human plasma (preheparin), since it is hydrolyzed by BChE. In fact, purified human serum BChE cleaves O,O,S-TB, although about 15-fold slower than butyrylthiocholine (standard assay conditions referred to earlier; data not shown).
OP SAR (Table 2).
Five 4-nitrophenyl phosphates (including paraoxon) with C2–C8 alkoxy substituents (1–5) are potent inhibitors (IC50 50–170 nM). Three analogs with longer (C12) substituents (6–8) are less active. Three fenitrothion oxon analogs (ethyl, pentyl, and isopropyl) (9–11) have similar potency (IC50 57–76 nM), while the pentyl substituents (12) double the potency of dichlorvos (13). CPO (17) and two analogs (pentyl and isopropyl) (14, 16) also have similar activity (IC50 78–94 nM). Four fluorophosphorus compounds (18–21) are potent (IC50 97–180 nM) while 22 and a methylphosphonate with a long (C13) chain (24) are moderately active (IC50 550–670 nM), but two alkylphosphonates with shorter (C5 and C8) chains (27, 28) have reduced activity (IC50 4–11 µM). Three benzodioxaphosphorin oxides (BDPOs) (29–31) and diazoxon (32) are potent inhibitors (IC50 67–200 nM).
Lipoprotein Lipase
Bovine milk OP SAR (Table 2).
Fourteen phosphates, including paraoxon, dichlorvos, CPO, diazoxon, fenitrothion-ethyl analogs, and diisopropyl fluorophosphate (DFP), have moderate to low potency (IC50 > 1 µM). However, several fluorophosphorus compounds are very potent inhibitors. Thus, EOPF (19) and a methylphosphonate with a C12 substituent (25) are the most potent inhibitors examined (IC50 7–9 nM), and four others (18, 23, 24, 26) are also very active (IC50 18–64 nM). Activity is retained for methylphosphonates with long chains (C11–C14) (23–26), but diminishes for C8 (27). O-octyl (30) and heptyl (31) BDPO are very active (IC50 15 nM), but the S-pentyl analog (29) is 28-fold less active.
Pseudomonas OP SAR (Table 2).
In the 4-nitrophenyl series, dioctyl (4) is most potent (IC50 150 nM). Dipentyl and didodecyl analogs (2, 8) are 53- and 31-fold less active, respectively, whereas diisopropyl (3) and diethyl (paraoxon) (5) are inactive. Replacement of one octyl with isopropyl (1) in the dioctyl compound (4) reduces LPL inhibitory activity 80-fold. Although fenitrothion-ethyl oxon (9) is potent for postheparin serum lipolytic activity, it is inactive for Pseudomonas LPL, but its dipentyl analog (10) is weakly active (IC50 27 µM). In the trichloropyridinyl series, CPO (17) is moderately active (IC50 2.2 µM). The dipentyl analog (14) is 16-fold more active, but dibutyl (15) is similar (IC50 2.5 µM), and diisopropyl (16) is inactive. For fluorophosphorus compounds, DFP (20) is weakly active (IC50 ca. 100 µM), and its dipentyl analog (21) is inactive. EOPF (19) has moderate activity (IC50 3.5 µM), but IDFP (18) is inactive. Methylphosphonates are active (IC50 160–170 nM) for C12–C14 alkoxy groups (23–25), decreasing 4-fold for C11 (26) and >30-fold for C8 (27). The S-pentyl, O-octyl, and heptyl BDPOs (29–31) tested are moderately active (IC50 2–6 µM). Dichlorvos (13), its dipentyl analog (12), and diazoxon (32) are inactive. Thus, five OP compounds are potent inhibitors of Pseudomonas LPL (IC50 140–170 nM). In general, longer alkoxy groups, C5–C14, are preferred whereas branched isopropyl groups greatly reduce activity.
Other Lipases
Pancreatic lipase OP SAR (Table 2).
The only highly potent inhibitor discovered is dioctyl 4-nitrophenyl phosphate (4) (IC50 8 nM). Activity is very sensitive to alkyl chain length with a >2000-fold decrease for the following changes: one n-C8 to i-C3 (1); two n-C8 to two n-C5 (2) or n-C12 (8). Eight oxon analogs in the fenitrothion, dichlorvos and chlorpyrifos series (9–16) are almost inactive, although CPO itself (17) has weak activity (IC50 20 µM). In the fluorophosphorus and BDPO groups, four alkyl methylphosphonates (C11–C14) (23–26) are fairly strong inhibitors (IC50 210–650 nM) with C12 (25) most active, while the other compounds are less active.
MAG lipase OP SAR (Table 2).
Twenty-two new OPs were tested for mouse brain MAG lipase inhibition and compared to 10 others from our previous studies (Quistad et al., 2006). 4-Nitrophenyl methyldodecylphosphinate (6) is the most potent OP yet tested (IC50 0.6 nM). Fenitrothion isopropyl oxon (11) and S-pentyl BDPO (29) of the new series are also very potent (IC50 3–4 nM).
Cholesterol esterase OP SAR (Table 2).
Cholesterol esterase (bovine pancreas) is very sensitive to all of the classes of OPs tested with a great variety of alkyl chain lengths (IC50 < 10 nM for 17 compounds). Seven OPs (1, 2, 4, 10, 12, 14, 15) are particularly active (IC50 0.7–1.9 nM).
KIAA1363 OP SAR (Table 2).
3H-CPO binding to KIAA1363 in mouse brain is also sensitive to many classes of OPs, i.e., 4-nitrophenyl, 3-methyl-4-nitrophenyl, trichloropyridinyl, and fluorophosphorus compounds. Of the fourteen new compounds tested, many have potency (IC50 8–14 nM) similar to our previous investigation (Nomura et al., 2005), but improved activity occurs for phosphate 1 and phosphinate 6 (IC50 3–4 nM).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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Each Lipase has a Unique OP Sensitivity Profile
Lipases show a wide range of sensitivities to OPs (Table 2). Some of the differences may be related to varying species and degrees of enzyme purification, leading to an emphasis on sensitivity profiles more than individual potencies. The IC50 values for each of the lipases (postheparin serum, bovine milk, Pseudomonas, pancreatic, MAG), cholesterol esterase, and KIAA1363 binding were plotted (log-log scale) against each other individually. The best correlation of these sensitivity profiles for lipases occurred for Pseudomonas versus pancreatic assayed with O,O,S-TB (r2 = 0.74, n = 15), and the next best for inhibition of cholesterol esterase hydrolytic activity versus KIAA1363 binding of OPs (r2 = 0.52, n = 20). In general, activity correlates poorly, and each lipase has a unique sensitivity profile for OP inhibitors.
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Potency of OP Pesticides Compared with Designer Compounds
Of the OPs studied, CPO is generally the most potent pesticide-related inhibitor of serine hydrolases (Fig. 1), justifying the focus on chlorpyrifos in studies of secondary targets in OP safety (Casida and Quistad, 2004
). Paraoxon, diazoxon, and dichlorvos are less active overall, inhibiting serine hydrolases in decreasing order. Even though DFP is the prototype serine hydrolase inhibitor, it generally is only moderately potent [except for BChE and acylpeptide hydrolase (APH)]. DFP is only a moderate inhibitor of brain AChE in vitro, which is surprising considering its high toxicity to mice (ip and as vapor) (Quistad et al., 2005b). The designer compounds IDFP and EOPF are the best general serine hydrolase inhibitors with multiple high-sensitivity targets. Their high potency is probably derived from a similarity to lipase substrates (C8 and C12 chain) without the long chain (C16–C20) which compromises solubility.
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Sensitivity of Lipases Compared with Other Serine Hydrolases
Eight OPs representative of pesticides (CPO, diazoxon, paraoxon, dichlorvos), fluorophosphorus acute (DFP) and delayed toxicants (EOPF and IDFP) and a cyclic phosphonate (phenyl-BDPO) were compared for potency using the lipase data from this investigation, new data from two serine hydrolases (long-chain acyl-CoA hydrolase and urokinase-type plasminogen activator), and the literature for numerous past studies from this laboratory (Fig. 1 and Supplementary Table 2). Interestingly, for none of the OPs examined was AChE the most sensitive target. The most sensitive enzymes for the active oxons from the pesticides are BChE and porcine liver esterase, generally followed by cholesterol esterase and KIAA1363. For the delayed toxicants (IDFP and EOPF), NTE-LysoPLA is most sensitive, with three orders of magnitude lower potency for AChE. Although PAF-AH is not very sensitive to the OPs tested here, potent methylphosphonates are known (Quistad et al., 2005a
). Digestive peptidases (except DFP with APH), blood clotting factors, and plasminogen activators (tissue-type and urokinase) are weakly inhibited by the OPs. Long-chain acyl CoA hydrolase is not inhibited by CPO, IDFP, EOPF, or phenyl-BDPO (IC50 > 100 µM). Urokinase is inhibited moderately to weakly by DFP, IDFP, EOPF, and phenyl-BDPO (IC50 4–30 µM) but not by the pesticides or oxon metabolites (IC50 > 100 µM).
Toxicological Implications of OP-Sensitive Lipase Targets
Some OP pesticides cause changes in lipid metabolism. Degradation of 2-arachidonoylglycerol in the cannabinoid system is disrupted by chlorpyrifos (30 mg/kg) inhibition of MAG lipase, leading to hypomotility, in part from interference with this signal transduction pathway (Quistad et al., 2006). Fenitrothion at 50 mg/kg increases triacylglycerols and certain phospholipids in liver, kidney, and brain of rats (Roy et al., 2004). A 50% LD50 dose of dichlorvos significantly inhibits postheparin lipolytic activity in rat plasma and increases triacylglycerols (Kozlowska et al., 1988; Luci
et al., 2002). Thus, at high doses these OP pesticides elevate blood triacylglycerols, which may have undesirable consequences to health, but the overall impact of lipase inhibition is probably minimal compared to the ramifications of AChE or NTE-lysoPLA inhibition, causing acute and delayed neurotoxicity, respectively. The effects on lipases from chronic exposure to OP pesticides are unknown.
There are many tissue and enzyme targets or detoxification sites for OPs following ingestion, inhalation, or dermal exposure (Fig. 2) (Casida and Quistad, 2004; Chambers et al., 2001). Digestive proteases and pancreatic lipases are fairly insensitive, whereas cholesterol esterase is strongly inhibited. Liver esterase has a high affinity for OPs. As OPs enter systemic circulation, BChE is a major serine hydrolase protectant, although postheparin serum lipase is moderately reactive. Reaction with brain APH, esterases, FAAH, KIAA1363, MAG lipase, and PAF-AH may neutralize OP toxicants and thereby reduce AChE and NTE-LysoPLA inhibition. Thus, several serine hydrolases with high OP reactivity may protect sensitive nerve targets from toxicity.
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SUPPLEMENTARY DATA |
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Supplementary data are available online at http://toxsci.oxfordjournals.org/. Heparin-induced serum lipolytic activity is differentiated by ethephon inhibition for BChE activity (Supplementary Table 1). The sensitivity of 28 serine hydrolases to eight organophosphorus compounds is given as IC50 values (Supplementary Table 2).
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ACKNOWLEDGMENTS |
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This work was supported by Grant R01 ES08762 from the National Institute of Environmental Health Sciences (NIEHS), NIH, and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. We thank our laboratory colleagues Rebecka Klintenberg and Hui-Wen Shih for assistance. The authors declare that there are no conflicts of interest.
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