Changes in the levels and forms of rat plasma cholinesterases during chronic diisopropylphosphorofluoridate intoxication

Traina, M.E.; Serpietri, L.A.

doi:10.1016/0006-2952(84)90321-6

Cited by 35 publications

(25 citation statements)

References 33 publications

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“…The latter outcome is in accordance with recent data from Jakubowski et al (2001) in experiments with VX-inhibited human serum, but stands in contrast with results of De Jong and Van Dijk (1984), who observed that reactivation with fluoride ions of GD-inhibited carboxylesterase in rat plasma becomes substantially less effective when the pH is raised from 4.8 to 6.1. However, the latter result may explain why Jakubowski et al (2001) observed a substantial decrease in yield of phosphofluoridate upon incubation of VXinhibited rat serum with fluoride ions, since serum of this species contains, in addition to BuChE and AChE (Traina and Serpietri 1984), a high concentration (2.6 lM) of CaE which is readily reactivated with fluoride ions after inhibition with OP anticholinesterases (De Jong and van Dijk 1984). In contrast with reactivation with oximes, reactivation with fluoride ions is not hampered in the acidic pH-range by the need to have the reactivating entity in its reactive anionic form since the pK a of HF is 3.2.…”

Section: Discussionmentioning

confidence: 83%

Retrospective detection of exposure to nerve agents: analysis of phosphofluoridates originating from fluoride-induced reactivation of phosphylated BuChE

Schans¹,

Polhuijs²,

Dijk³

et al. 2004

Arch Toxicol

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The utility was explored of a new approach to detect retrospectively exposure to nerve agents by means of conversion of the inhibitor moiety bound to the active site of the enzyme BuChE in plasma with fluoride ions into a phosphofluoridate which is subsequently analyzed by means of gas chromatography (GC). This quantifies >or=0.01% inhibition of BuChE and identifies the structure of the inhibitor except for the original leaving group. A three-tiered approach was followed involving the five classical nerve agents GA, GB, GF, GD, and VX, as well as the active metabolite of parathion, i.e., paraoxon: in vivo experiments in rhesus monkeys after iv administration of a sign-free dose of agent and concomitant in vitro experiments in plasma of rhesus monkeys and humans should allow an assessment of in vivo retrospectivity in humans. A systematic investigation was performed in order to find a single set of reaction conditions which yields a maximum amount of phosphofluoridate for all nerve agents. Fluoride-induced reactivation at 25 degrees C at a final concentration of 250 mM KF during 15 min in a pH-range between 4 and 6 appears to be effective. The in vitro decrease with time in reactivatibility of inhibited BuChE in plasma from humans and rhesus monkeys was largely due to aging of the phosphyl moiety, except for VX where spontaneous reactivation was a major cause. The decrease followed first-order except for a biphasic course in the case of GF in human and rhesus monkey plasma as well as of GD in rhesus plasma. In vitro half-lifes in human plasma ranged between ca. 14 h for GB and ca. 63 h for GA. A comparison of the in vivo data from rhesus monkeys and the in vitro data is complicated by the observation that the in vivo decrease with time of fluoride-reactivated phosphofluoridate is biphasic for all nerve agents. The terminal in vivo phase pertains to a small fraction of the amount of initially regenerated phosphofluoridate but is responsible for a considerable degree of retrospectivity, ranging between 14 and 56 days for GF and GB, respectively. The new procedure can be used in a variety of practical applications, e.g., (i) biomonitoring in health surveillance at exposure levels that are several orders of magnitude lower than presently possible; (ii) diagnosis in case of alleged exposure to nerve agents in time of war or after terrorist attacks; (iii) in forensic cases against suspected terrorists that have handled organophosphate anticholinesterases; and (iv) in research applications such as investigations on lowest observable effect levels of exposure to nerve agents.

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Section: Discussionmentioning

confidence: 83%

Retrospective detection of exposure to nerve agents: analysis of phosphofluoridates originating from fluoride-induced reactivation of phosphylated BuChE

Schans¹,

Polhuijs²,

Dijk³

et al. 2004

Arch Toxicol

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“…Furthermore, it is difficult to extrapolate plasma ChE results from animals to humans, since the enzymes that constitute plasma ChE activity vary from species to species. In rats, plasma ChE activity is approximately 50% butyryl-and 50% acetyl-cholinesterase while in humans it is 100% butyrylcholinesterase (Traina and Serpietri, 1984;Padilla et ai, 1994). On the other hand, inhibition of these enzyme activities may predict AChE activity in brain and/or muscle tissue, especially under the conditions of these studies, where rapid changes are not expected (Padilla et ai, 1994).…”

Section: Discussionmentioning

confidence: 99%

Subchronic Neurotoxicity Screening Studies with Six Organophosphate Insecticides: An Assessment of Behavior and Morphology Relative to Cholinesterase Inhibition

et al. 1997

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Sulprofos, disulfoton, azinphos-methyl, methamidophos, trichlorfon, and tebupirimphos were screened for neurotoxic potential, in accordance with U.S. EPA (FIFRA) requirements. Each organophosphate was administered through the diet for 13 weeks to separate groups of Fischer 344 rats at four dose levels, including a vehicle control. For each study, 12 rats/sex/dietary level were tested using a functional observational battery (FOB), automated measures of activity (figure-8 maze), and detailed clinical observations, with half of the animals perfused at term for microscopic examination of neural and muscle tissues. Separate groups of satellite animals (6/sex/dietary level) were used to measure the effect of each treatment on plasma, erythrocyte (RBC), and brain cholinesterase (ChE) activity. The results show that measures of ChE activity were consistently the most sensitive indices of exposure and assisted in the interpretation of findings. All treatment-related neurobehavioral findings were ascribed to cholinergic toxicity, occurring only at dietary levels that produced more than 20% inhibition of plasma, RBC, and brain ChE activity. Neurobehavioral tests provided no evidence of additional cumulative toxicity after 8 weeks of treatment. The FOB and motor activity findings did not alter the conclusions and generally did not reduce the neurobehavioral no-observed-effect level (NOEL) for any of the six compounds, relative to the results from detailed clinical observations as conducted in these studies. The one exception occurred with tebupirimphos, where the NOEL for motor activity was one dose level lower than the NOEL for the FOB and clinical observations. These results support the value of detailed clinical observations to screen for the neurotoxic potential of organophosphates and a general standard of more than 20% inhibition of brain ChE activity for cholinergic neurotoxicity. © 1997 society of Toxicoio g5 .

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“…The zero-order synthesis rates and first-order loss rates for BESTs in rat plasma and in mice were estimated by fitting simulations to data describing the rate of return of enzyme activity to normal levels over time after DFP dosing (see "Results"). The synthesis and loss rates used for AChE were also used for BChE and CaE since the rate of increase of these activities after OP inhibition is close to that ofAChE (25,26).…”

Section: Diisopropylfluorophosphate Binding To Esterasesmentioning

confidence: 99%

“…Martin (34) found, however, that 7 days after a single iv injection of 1 mg DFP/kg, brain AChE activity in the mouse was only about 80% of the preexposure level (Figure 5c). (25) measured the effect of DFP on plasma AChE activity using the same rat strain and dosing regimen as Michalek (24). Traina and Serpietri (25) found that plasma AChE activity in the rat fell rapidly after sc injection of DFP (Figure 6a (Figure 7a,b).…”

Section: Partiton Coefficientsmentioning

confidence: 99%

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Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters.

Gearhart¹,

Jepson²,

Clewell³

et al. 1994

Environ Health Perspect

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Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would greatly improve OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed. DFP tissue/blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain, as well as AChE inhibition and AChE resynthesis data, were successfully simulated for a single iv injection. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain were also well simulated except for an apparent decrease in basal AChE activity in the brain which persisted 35 days after the last dose. The psychologically based pharmacokinetic (PBPK) model parameter values specific for DFP in humans, for example, tissue/blood partition coefficients, enzymatic and nonenzymatic DFP hydrolysis rates, and bimolecular inhibition rate constants for target enzymes were scaled from rodent data or obtained from the literature. Good agreement was obtained between model predictions and human exposure data on the inhibition of red blood cell AChE and plasma butyrylcholinesterase after an intramuscular injection of 33 pg/kg DFP and at 24 hr after acute doses of DFP (10-54 pg/kg), as well as for repeated DFP exposures. The PBPK model for DFP was also adapted for the purpose of modeling parathion, including its metabolism to the toxic daughter product paraoxon. The development and validation of this PBPK model for two OPs provides a basis for studying the kinetics and in vivo metabolism of other bioactivated organophosphate pesticides and their pharmacodynamic effect in humans. -Environ Health Perspect 102(Suppl 11):51-60 (1994)

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Changes in the levels and forms of rat plasma cholinesterases during chronic diisopropylphosphorofluoridate intoxication

Cited by 35 publications

References 33 publications

Retrospective detection of exposure to nerve agents: analysis of phosphofluoridates originating from fluoride-induced reactivation of phosphylated BuChE

Retrospective detection of exposure to nerve agents: analysis of phosphofluoridates originating from fluoride-induced reactivation of phosphylated BuChE

Subchronic Neurotoxicity Screening Studies with Six Organophosphate Insecticides: An Assessment of Behavior and Morphology Relative to Cholinesterase Inhibition

Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters.

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