Plasma Aliesterases Research Articles

Effects of Piperonyl Butoxide on the Metabolism of DEF S,S,S-Tributyl Phosphorotrithioate) in Fingerling Channel Catfish

The present study was undertaken to investigate the significance of monooxygenases in bioactivation of DEF to a more effective anticholinesterase in fish. Channel catfish were exposed via the water column for 20 h to piperonyl butoxide (PBO) followed by a 4-h exposure to the organophosphate defolient DEF (concurrent with the PBO). Acetylcholinesterase (AChE) and aliesterases (ALiEs) activities were determined at 0 and 12 h after the exposure period. Inhibition of brain, liver, and plasma AChE activity by DEF was antagonized by PBO; muscle AChE was not inhibited by DEF. Piperonyl butoxide did not antagonize the inhibition of liver or plasma ALiEs by DEF. These results suggest that PBO retards the formation of the metabolite(s) of DEF that inhibit AChE, and that DEF is an effective inhibitor of ALiEs without metabolic activation.

Inhibition of acetylcholinesterase and aliesterases of fingerling channel catfish by chlorpyrifos, parathion, and S, S, S-tributyl phosphorotrithioate (DEF)

Serine esterases can be inhibited by organophosphorus compounds. The in vitro potency of the organophosphorus pesticide DEF and oxons of the phosphorothionate insecticides chlorpyrifos (chlorpyrifos-oxon, Cpxn) and parathion (paraoxon, Pxn) were determined for brain, gill, liver, muscle, and plasma for acetylcholinesterase (AChE) and gill, liver, and plasma aliesterases (ALiE). AChE activity was inhibited less than 15% in all tissues in the presence of 1 mM DEF ®. AChE I 50 values for Cpxn were 28–33 nM, and for Pxn were 446–578 nM. ALiE I 50 values for Cpxn were 0.1–0.2 nM, for DEF were 24–163 nM, and for Pxn were 6–46 nM. Fish were exposed to chlorpyrifos (Cp), parathion (Pth), DEF, and combinations of the phosphorothionates with DEF for 4 h followed by a 384-h recovery period. AChE inhibition following Cp and Pth exposures was rapid. Cp led to more persistent inhibition than Pth. DEF treatments yielded low levels of AChE inhibition in brain and muscle, and high levels of inhibition in gill, liver, and plasma. In vitro and in vivo results suggest that DEF's disposition and/or mode of action are different than those of Cp or Pth. Exposure to DEF resulted in persistent, high level inhibition of ALiE activity. Greater AChE inhibition in DEF plus Cp or Pth treatments was not evident, suggesting that ALiEs do not serve to appreciably protect AChE in channel catfish, even though ALiEs are inherently more sensitive to inhibition.

Inhibition Patterns of Brain Acetylcholinesterase and Hepatic and Plasma Aliesterases Following Exposures to Three Phosphorothionate Insecticides and Their Oxons in Rats

Inhibition Patterns of Brain Acetylcholinesterase and Hepatic and Plasma Aliesterases Following Exposures to Three Phosphorothionate Insecticides and Their Oxons in Rats. Chambers, J. E., and Carr, R. L. (1993). Fundam. Appl. Toxicol. 21, 111-119.Rats were administered high sublethal intraperitoneal dosages of the phosphorothionate insecticides parathion, methyl parathion, and chlorpyrifos, and their oxons. Acetylcholinesterase activities in cerebral cortex and medulla oblongata and aliesterase activities in liver and plasma were monitored at 2 hr and 1, 2, and 4 days after exposure. The maximal inhibition of brain acetylcholinesterase activity was not immediate with parathion and chlorpyrifos, reflecting the time required for bioactivation of the phosphorothionates as well as the effectiveness of the aliesterases to inactivate much of the hepatically generated oxons. In contrast, brain acetylcholinesterase activities were more quickly inhibited following administration of paraoxon and chlorpyrifos-oxon, which do not require bioactivation. Brain acetylcholinesterase was also rapidly inhibited following administration of methyl parathion and methyl paraoxon, reflecting the low sensitivity of the aliesterases to methyl paraoxon. Aliesterases were inhibited to a greater extent than acetylcholinesterase at each sampling time with parathion and chlorpyrifos and their oxons, whereas the reverse was true with methyl parathion and methyl paraoxon. All of the above patterns correlate with the in vitro sensitivities of acetylcholinesterase and aliesterases to the oxons. The very prolonged inhibition of esterase activities following chlorpyrifos treatment probably results from its substantially greater lipophilicity compared to the other compounds, which would allow it to be stored and released for gradual bioactivation. The data reported indicate that the disposition and effects of different phosphorothionate insecticides will be influenced by the sensitivities of target and nontarget esterases for their oxons and by their lipophilicity, and that predictions of in vivo responses can be made from in vitro data.

Inhibition Patterns of Brain Acetylcholinesterase and Hepatic and Plasma Aliesterases Following Exposures to Three Phosphorothionate Insecticides and Their Oxons in Rats

Inhibition Patterns of Brain Acetylcholinesterase and Hepatic and Plasma Aliesterases Following Exposures to Three Phosphorothionate Insecticides and Their Oxons in Rats

Acute effects of the organophosphate paraoxon on schedule-controlled behavior and esterase activity in rats: Dose-response relationships

The effects of acute intraperitoneal administration of paraoxon on behavioral and biochemical parameters were studied in male rats. Rats were trained to press a lever under an FR10 schedule of reinforcement. Rats were injected with 3 sublethal doses of paraoxon (0.5, 0.75, and 1.0 mg/kg) and performance was monitored for four days after exposure. Response rates were depressed significantly for days 1 and 2 with 0.75 and 1.0 mg/kg, but not 0.5 mg/kg, even though there was inhibition of brain and plasma cholinesterases at all doses. Performance recovered prior to brain AChE recovery. There was no clear-cut threshold of brain AChE inhibition required to yield performance deficits, nor was there a direct correlation between significant inhibition in peripheral enzymes which could serve as markers (plasma aliesterases, butyrylcholinesterase, non-iso-OMPA-sensitive cholinesterase, and hepatic aliesterases) and performance deficits, suggesting that other noncholinergic targets may play a role in OP-induced behavioral deficits.

Target site bioactivation of the neurotoxic organophosphorus insecticide parathion in partially hepatectomized rats

Target organ bioactivation of phosphorothionate insecticides to their potent anticholinesterase oxon metabolites (for example, parathion to paraoxon) may be extremely important in toxicity because liver and blood provide so much potential protection by a variety of mechanisms, such as the aliesterases which serve as alternate phosphorylation sites. To determine whether the brain can produce sufficient oxon in vivo to contribute to toxicity, male rats were partially hepatectomized and injected i.v. with 1.5 mg/kg parathion. After 30 minutes, brain AChE was inhibited 68% whereas liver and plasma aliesterases were unaffected. Because aliesterases are far more sensitive to paraoxon inhibition than is brain AChE, these results indicate that neither the liver nor extra-hepatic tissues were contributing oxon into the blood stream. Thus target site activation of parathion occured in vivo at sufficient levels to contribute substantially to toxicity.

Time course of inhibition of acetylcholinesterase and aliesterases following parathion and paraoxon exposures in rats

The inhibition of cerebral cortex and medulla oblongata acetylcholinesterase and hepatic and plasma aliesterases was studied in female rats following intraperitoneal administration of the phosphorothionate insecticide parathion or its active metabolite paraoxon. Acetylcholinesterase is the target enzyme for organophosphate toxicity while aliesterases are alternative targets for organophosphate inhibition which could serve in a protective capacity during organophosphate intoxication. The effects of pretreatment with cytochrome P450 inducers and inhibitors were also investigated. Pretreatment with phenobarbital slowed the time course of acetylcholinesterase and hepatic aliesterase inhibition following parathion exposure, suggesting the induction of a detoxication pathway(s) to a greater extent than the induction of activation. Although pretreatment with piperonyl butoxide did not affect the rate of acetylcholinesterase inhibition, it slowed hepatic and plasma aliesterase inhibition following parathion administration, presumably from inhibition of the parathion activation pathway. In rats pretreated with β-naphthoflavone (BNF), hepatic aliesterases demonstrated lower specific activity; additionally, there was a reduced level of inhibition in BNF-pretreated rats following either parathion or paraoxon administration. However, any effects of BNF on parathion- or paraoxon-induced inhibition cannot be distinguished at this time from the effects of the oil vehicle, which reduced esterase inhibition, presumably by its ability to sequester the organophosphate. Brain acetylcholinesterase was partially inhibited before the hepatic aliesterases were maximally inhibited in all treatment groups. In most cases, plasma aliesterases were maximally inhibited within 15 min after organophosphate administration. Thus hepatic aliesterases constitute an important but not completely effective form of protection from the inhibitory effects of organophosphates.

Soman intoxication in hypothyroid rats: alterations in brain neuronal RNA, acetylcholinesterase and survival

Studies were conducted to investigate relationships among soman (pinacolyl methylphosphonofluoridate) induced seizure activity, central metabolic impairments and lethality in normal vs thyroid-deficient rats. Quantitative cytophotometric measurements of individual cerebrocortical (layer V) and striatal neuron RNA contents were made following dosages of 0.5, 0.9 and 1.5 LD(50) soman (LD(50) = 135 ?g/kg, sc). Hypothyroidism was associated with a marked diminution of overt convulsive activity and reduced susceptibility to lethal actions of soman as indicated by enhanced 24- and 48-h survival rates at 0.9, 1.2 and 1.5 LD(50). Hypothyroidism per se produced RNA depletion in both cortical and striatal neurons. Soman treatment diminished cortical RNA to essentially the same extent in thyroid-deficient rats as in euthyroids, whereas there was no further reduction of striatal neuron RNA. It was found that amelioration of convulsive activity and lethal- ity in hypothyroid rats was accompanied by reduced cerebral acetylcholinesterase (AChE, EC 3.1.1.7) inactivation, and that plasma cholinesterase (EC 3.1.1.8) and aliesterase (EC 3.1.1.1) levels were significantly higher in hypothyroid than in euthyroid saline-control rats. The overall data indicate that soman- induced central metabolic impairments can occur independent of paroxysmal neural activity and lethal actions of the agent. Resistance to soman observed with thyroid deficiency may be due in large part to increased binding to plasma enzymes and diminished delivery of soman to AChE in vital cholinergic sites.

Importance of aliesterase as a detoxification mechanism for soman (pinacolyl methylphosphonofluoridate) in mice

CBDP (2−/ O-cresyl/4 H: 1 : 2-benzodioxaphosphorin-2-oxide) pretreatment produced a dramatic increase in the toxicity of soman in mice following the subcutaneous (s.c.) or intraperitoneal (i.p.) route of administration. This increase in soman toxicity was very highly correlated with inhibition o plasma aliesterase activity. Other enzymes (e.g. liver aliesterase and plasma cholinesterase) were inhibited by CBDP pretreatment; however, they did not appear to play a significant role in the potentiation of soman toxicity by CBDP. Liver aliesterase was not inhibited by doses of CBDP which produced significant increases in soman toxicity. Similarly, doses of Iso-OMPA, a selective inhibitor of pseudocholinesterase, which completely inhibited plasma cholinesterase, had no effect on soman toxicity. Pyridostigmine pretreatment which inhibited brain, diaphragm and plasma acetylcholinesterase 27, 57 and 60%, respectively, while not inhibiting plasma aliesterase, did not affect soman toxicity. The results of this study demonstrate that, in mice, plasma aliesterase is an extremely important detoxification route for soman.

Role of aliesterase in organophosphate poisoning

Various doses of CBDP (2-(2-methylphenoxy)-4 H-1,3,2-benzodioxaphosphorin-2-oxide), a metabolite of tri- o-cresyl phosphate, increased dramatically the acute toxicity of soman (pinacolyl methylphosphonofluoridate) in mice. CBDP (5 mg/kg; iv) reduced the soman LD50 value from 136 μg/kg in control to 6.95 μg/kg. The potentiation of soman toxicity following CBDP pretreatment appeared to be due primarily to inhibition of plasma aliesterase activity. Inhibition of liver aliesterase was not of primary importance in the potentiation of soman toxicity following CBDP pretreatment. In addition pretreatment with ISO-OMPA (tetraisopropyl pyrophosphoramide), a selective inhibitor of pseudocholinesterase, had no effect on the acute toxicity of soman. Similarly pretreatment of mice with pyridostigmine, a quaternary carbamate anticholinesterase which does not inhibit aliesterase, resulted in marked inhibition of diaphragm, plasma, and brain acetylcholinesterase had no effect on the acute toxicity of soman. Plasma aliesterase may be a depot for soman poisoning. The acute toxicity of soman by the ip, sc, and iv routes of administration was reduced following pretreatment of mice with phenobarbital (100 mg/kg) for 4 days. The reduced toxicity of soman following phenobarbital pretreatment was due to induction of liver aliesterase activity which subsequently resulted in an increase in plasma aliesterase activity. Thus more soman was probably bound to plasma aliesterase activity resulting in a reduction in acute toxicity of soman. Conversely pretreatment of mice with pentobarbital (70 mg/kg; ip) increased the toxicity of soman. This was probably the result of inhibition of plasma aliesterase by pentobarbital pretreatment combined with the central respiratory depression following pentobarbital administration. Following pentobarbital pretreatment soman inhibition of brain acetylcholinesterase was increased suggesting that plasma aliesterase inhibition alters the distribution of free soman in vivo. In summary, in mice plasma aliesterase appears to be an extremely important detoxification route for soman in vivo.

Plasma aliesterase — A possible depot for soman (Pinacolyl methylphosphonofluoridate) in the mouse

Plasma aliesterase — A possible depot for soman (Pinacolyl methylphosphonofluoridate) in the mouse

Factors modifying the toxicity of organophosphorus compounds including dichlorvos.

The effect of repetitive doses of organophosphorus agents in experimental animals has been studied. The cumulative LD50 dose depended upon the time interval between injections of toxic agent. From these data it was possible to obtain the rate of detoxification of these agents. In the case of soman and sarin TOCP pretreatment, an inhibitor of plasma aliesterase, modified both the acute LD50 and the rate of detoxification. The results therefore suggest that recovery of plasma aliesterase contributes to a large extent in detoxification of chronically administered soman and sarin. In contrast, tolerance to chronically administered dichlorvos can not be correlated to recovery of plasma aliesterase, but correlates well with a rapid spontaneous reactivation of acetylcholinesterase.

Toxicity of soman after repetitive injection of sublethal doses in guinea-pig and mouse.

Injection of sublethal doses of soman in guinea-pig and mouse subcutaneously every 3.5, 8, 12 or 24 hours led to cumulative LD50 doses which were markedly higher than the acute one. When animals were exposed every 24 hrs to half LD50 doses of soman, a majority of guinea-pigs but relatively few mice, survived a total exposure of 5-6 times the acute LD50 dose. Guinea-pig brain and diaphragm acetylcholinesterase activities declined steadily during the repeated soman exposure. Plasma cholinesterase activity was less than 10% 1 hr after soman injection, but was restored to 40-50% of control within 24 hrs. Liver aliesterase activity was not significantly inhibited by soman, whereas plasma aliesterase activity was 70% inhibited after 1 hr and restored to control level within 24 hrs. TOCP treatment of guinea-pig led to 3-fold increase in acute soman toxicity, and reduced their tolerance from more than 6 lD50 to 2.5 LD50 dose of soman. It is included that the recovery of plasma aliesterase and cholinesterase play an important part in the observed tolerance towards repeated soman treatment.