Administration Of Parathion Research Articles

An unusual case of attempted suicide by rectal administration of parathion

Although organophosphate (OP) poisoning is well known, unusual routes of administration of OP compounds are reported occasionally. Herein, a case of self administration of parathion, an OP compound, into the rectum using a six inches (15 cm) nozzle of a sprayer in a 35-year-old man is highlighted along with probable mechanisms for rapid absorption and severe systemic toxicity.

Effect of subacute methyl parathion administration on the pharmacokinetics and pharmacodynamics of nifedipine in rats

Families living in agricultural areas may submitted to repeated exposure of methyl parathion (MP) that has been widely used as an agricultural insecticide. MP inhibits cytochrome P450 enzymes and has the potential to alter pharmacokinetic profiles of therapeutic agents that are metabolized in the liver. The aim of the present study is to investigate the possibility that the increased pharmacokinetic and pharmacodynamic effects of nifedipine is due to the inhibition of the metabolism after repeated administration of low doses of MP in rats. Male rats received commercial formulation of diluted MP (1/100 LD 50 or 1/25 LD 50, n = 6) or tap water (control, n = 5) via gastric gavage (0.5 ml) for 14 days. On the 15th day, the carotid artery and jugular vein were cannulated for measurement of cardiovascular parameters and blood sampling, respectively. Nifedipine was administered 3 mg/kg via the cannula inserted in the duodenum of the rat. Subacute MP administration did not change pharmacokinetic AUC (0–240), C max, t max, t 1/2) and pharmacodynamic (mean arterial pressures and heart rates) parameters of nifedipine. These findings provide evidence that repeated exposure of low doses of commercial MP did not affect the elimination of nifedipine which might be due to the lack of inhibition of CYP3A in rats.

Effects of physostigmine on the pharmacokinetics of intravenous parathion in rats.

It was reported that the area under the plasma concentration-time curve from time zero to time infinity (AUC) of parathion was significantly smaller, and the time-averaged total body clearance (Cl) of parathion was significantly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats. This was supported by significantly faster intrinsic clearance of parathion to form paraoxon in hepatic microsomal fraction of rats pretreated with dexamethasone. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible hepatic cytochrome P450 (CYP) 3A in rats. The purpose of this study is to explain the protective effects of physostigmine against paraoxon toxicity by suppressing CYP3A, and hence, decreasing formation of a toxic metabolite, paraoxon. The pharmacokinetic changes of parathion and paraoxon were investigated after intravenous administration of parathion, 3 mg/kg, to control Sprague-Dawley rats, and the rats pretreated with physostigmine (100 microg/kg, intraperitoneal injection 30 min before parathion administration). After a 1-min intravenous infusion of parathion to rats pretreated with physostigmine, the AUC of parathion (60.4 compared with 73.7 microg min/mL) was significantly greater, Cl of parathion (49.7 compared with 40.7 mL/min/kg) was significantly slower, and amount of paraoxon recovered from liver, mesentery and large intestine at 5 min was smaller than those in control rats. Based on in vitro rat hepatic microsomal studies, physostigmine inhibited significantly the erythromycin N-demethylase activity (1.03 compared with 0.924 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in rats. The above data suggested that the formation of paraoxon was inhibited in rats pretreated with physostigmine by inhibiting CYP3A.

Possible involvement of beta-adrenergic receptors in the enhancement of nocturnal pineal N-acetyltransferase activity due to parathion administration

The purpose of the present study was to examine the effects of administration of sublethal doses of O, O-diethyl- O- p-nitrophenyl phosphorothioate (parathion) on serum epinephrine (EPI) and norepinephrine (NE), as well as on night-time rat pineal melatonin synthesis, both in the presence and absence of propranolol, a β-adrenergic receptor antagonist. In the first experiment, two groups of adult albino rats were administered parathion orally (1.08 and 2.17 mg/kg/day; the total received by each animal was 6.5 and 13.0 mg/kg body weight over 6 days); another two groups received corn oil only. Animals were killed at 23:00 and 01:00 h by decapitation. Serum EPI was augmented at 01:00 h, but NE was increased at 01:00 and 23:00 h due to administration of the high dose of parathion (13 mg/kg). In the second experiment, two groups of adult male albino rats were administered parathion orally (13 mg/kg); another two groups received an intraperitoneal injection of propranolol (20 mg/kg body weight, 1 h before the lights were turned off). In addition, two groups were given a saline injection. Four hours after darkness onset, pineal N-acetyltransferase (NAT) activity as well as pineal and serum melatonin levels were measured. Parathion by itself significantly augmented nocturnal pineal NAT activity and serum melatonin levels in otherwise untreated rats; the insecticide was ineffective in reference to this enzyme when it was given in conjunction with the β-adrenergic receptor antagonist propranolol. The augmentation of NAT activity by parathion also caused significant reduction in pineal serotonin (5-HT); again, this response was blocked by propranolol treatment. The results are consistent with the idea that parathion influences pineal 5-HT metabolism either at the level of the β-adrenergic receptor or via the sympathetic innervation to the pineal gland.

Parathion (O,O-dimethyl-O-p-nitrophenyl phosphorothioate) induces pineal melatonin synthesis at night

The effects of parathion on male rat pineal N-acetyltransferase (NAT) activity, hydroxyindole-O-methyltransferase (HIOMT) activity and pineal and serum melatonin levels at the end of light period (2000 h) and at night (2300 h and 0100 h) were studied. Additionally, pineal levels of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) were estimated. Parathion was administered intragastrically at total doses (over 6 days) of either 6.5 or 13 mg/kg. Control rats received vehicle (corn oil) only. During the study, the rats were exposed to light:dark cycles of 14:10 with light off at 2100 h. Pineal NAT activity was increased at 0100 h following parathion administration at both doses, but HIOMT activity was unaffected. Pineal and serum melatonin levels were increased at night (2300 h and 0100 h) after the 13 mg/kg dose of parathion while the lower dose increased pineal melatonin only at 0100 h. Also, both doses decreased 5-HTP at 2000 h while the lower dose increased it at 2300; 5-HT was significantly decreased at 2300 h and 5-HIAA levels were lower but only significantly so for the 13 mg/kg dose at 2000 h. The results indicate that parathion has significant effects on pineal melatonin synthesis by mechanisms which remain unknown.

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.

Effects of subchronic parathion administration on sodium salicylate excretion kinetics in female rats.

Organophosphorus (OP) pesticides are considered to be environmental contaminants, and chronic exposure to low levels through the diet may affect drug action. To study this possible interaction, ethyl parathion was administered by intubation to female rats for 35 consecutive days at a dose of 0.05 or 0.2 mg/kg of body weight per day. At 7, 21 and 35 days after parathion was initiated, rats were administered a single dose of 20 mg/kg sodium salicylate intraperitoneally. Total salicylates, salicylic acid (SA), salicyluric acid (SU) and gentisic acid (GA) were determined in urine. At 7 days, parathion treatment slowed the excretion of total salicylates. This effect was more evident at longer treatment times. Total excretion of SA was increased at the expense of GA at 7 days. However, this effect was reversed at 21 and 35 days. Excretion of SU was drastically diminished after 21 days of treatment with parathion. The results suggest that subchronic oral administration of parathion to female rats changes the excretion kinetics of sodium salicylate through combined effects on renal excretion mechanisms and biotransformation processes. Thus, exposure to low concentrations of environmental contaminants may produce important changes in drug action.

Urinary excretion kinetics of p-nitrophenol following oral administration of parathion in the rabbit.

The urinary excretion kinetics of p-nitrophenol were studied in rabbits following oral administration of parathion at a dose of 3 mg/kg. Elimination of p-nitrophenol began rapidly, and of the total amount excreted during the study period, 46% was excreted in the first 3 h; 85% was excreted at 6 h after administration of the pesticide. The mean maximum excretion rate of p-nitrophenol was 111.15 +/- 61.02 micrograms/h reached in a time of 0.77 +/- 0.26 h. The formation and disappearance rate constants of the metabolite were 2.85 +/- 2.80 h-1 and 0.80 +/- 0.28 h-1, respectively. A linear relationship was observed between the plasma concentrations of parathion and the urinary excretion rate of p-nitrophenol.

Dose-related neurochemical changes in the levels of gangliosides and glycogen in various regions of the rat brain and spinal cord following methyl parathion administration

The aim of the present study was to evaluate the neurochemical changes in the levels of gangliosides and glycogen of the cerebral hemisphere, cerebellum, brain stem and spinal cord following the intraperitoneal (ip) injection of the organophosphate pesticide methyl parathion (1.0 mg, 1.5 mg and 2.0 mg/kg) to each rat of the experimental group daily for 7 days. A remarkable dose-related depletion in the concentration of gangliosides was discernible in all the regions of the CNS. Also, the contents of glycogen exhibited a decrement in different parts of the brain with all the 3 dose-schedules following methyl parathion toxicosis. The results suggest that the levels of gangliosides and glycogen are affected dose-dependently in various regions of the rat brain and spinal cord.

Effect of parathion on water intake in the rat

The effect of several subtoxic doses of parathion on water intake was studied in conscious rats with centrally induced thirst. A potent and long-lasting antidipsogenic effect was obtained when single doses ranging from 100 to 600 μg of parathion/100 g body wt were ip given to rats in which thirst was induced either by 24 hr water deprivation or sc injection of hypertonic NaCl solution. A significant thirst inhibition was also obtained when paraoxon or dichlorvos (DDVP) was given. The antidipsogenic effect was prevented by the previous administration of diacetylmonoxime (DAM), an acetylcholinesterase reactivator, but not prevented by pralidoxime (2-PAM), another reactivator that is unable to cross the blood-brain barrier (BBB). Thirst inhibition induced by parathion administration was also prevented when muscarinic cholinergic blockers were previously given, such as atropine sulfate. Acetylcholinesterase activity (AChE) was not inhibited on either blood or hypothalamic tissue with the different doses of parathion given. Locomotor activity and emotionality also remained unaltered. The results obtained indicate that the antidipsogenic effect of the organophosphorus pesticide is centrally produced by stimulation of muscarinic cholinergic pathways.

Parathion toxicity in relation to liver microsomal oxidases, lipid composition and fluidity.

Rats were injected intraperitoneally with phenobarbital (PB) and 3-methylcholanthrene (MC), 80 and 20 mg/kg, respectively, for 3 consecutive days and then administered threshold lethal dose of the organophosphorus insecticide, parathion, 10 mg/kg i.p. to compare its toxicity in these, with those fed high fat, diet (HFD-50% saturated fat, and normal diet (ND-10% saturated fat) for 30 days. Hepatic microsomes of these four groups of rats without the parathion administration were also analysed to evaluate toxicity and metabolism of the insecticide in relation to some physico-chemical changes in microsomal membranes. Results showed that in comparison to ND, all three pretreatments (PB, MC and HFD) significantly decreased parathion toxicity, increased microsomal oxidase activity and elevated microsomal cholesterol/phospholipid ratio. However, microsomal cytochrome P-450 was significantly raised only in PB and MC, and microsomal fluidity was significantly raised only in MC, as measured by DPH-fluorescence polarization technique.

Mechanism of enhanced parathion/paraoxon toxicity during pregnancy in the mouse

The mechanism of enhanced parathion/paraoxon toxicity during pregnancy was examined. Enhanced toxicity following exposure to paraoxon in the pregnant mouse as determined by cholinesterase suppression was observed at 0.10 and 0.58 mg/kg after ip administration on Day 19 of gestation. However, there were no significant differences in cholinesterase activity between pregnant animals and virgin controls after either po or iv paraoxon. Higher systemic and lower hepatic levels of parathion were demonstrated in pregnant mice following ip administration of parathion (5 mg/kg). Data herein also suggest that during pregnancy, larger quantities of paraoxon bypass initial liver detoxification after ip dosing. The mechanism of increased toxicity of parathion/paraoxon during pregnancy may result from alterations in absorption from the peritoneal cavity.

Effect of high-fat and high-protein diets on toxicity of parathion and dichlorvos.

Growing male rats that weighed 120 +/- 5 g were kept for 30 days on the following synthetic diets: high protein diet (HPD), 59% casein; high fat diet (HFD), 50% saturated fat; and normal diet (ND), 19% casein, 10% saturated fat, and 60% sucrose. Other essential dietary ingredients were included in all the diets. All animals were injected at the end of the 30-day period with parathion [10 mg/kg intraperitoneal (ip) injection as a single dose] or dichlorvos (30 mg/kg ip as a single dose) to compare the effect of dietary pretreatments on mortality from parathion and dichlorvos. A lower dose of parathion (7.5 mg/kg) and dichlorvos (20 mg/kg) was employed in another set of experiments to compare the spontaneous regeneration of plasma and red blood cell (RBC) cholinesterase (ChE) activity at 2 hr, 1 day, 3 days, and 5 days after administration of parathion or dichlorvos. The effect of these diets on hepatic microsomal oxidases was also determined. Results showed that diets per se did not affect initial plasma and RBC ChE activity. The HPD and HFD significantly protected against mortality from parathion but not from dichlorvos. Hepatic microsomal cytochrome P-450 and aminopyrine demethylase activity were unchanged, but aniline hydroxylase activity was increased significantly by HPD and HFD. Parathion oxidase in hepatic microsomes was significantly increased in rats fed HFD only. For the HPD, spontaneous regeneration of ChE diminished in RBCs in parathion-intoxicated rats and in plasma and RBCs of dichlorvos-intoxicated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of pregnancy on parathion toxicity and disposition

The effects of pregnancy and lactation on the toxicity and distribution of parathion and paraoxon were examined. Signs of cholinergic stimulation were more intense in pregnant mice when compared to virgin controls after administration of parathion or its active metabolite, paraoxon. Cholinesterase activity and tissue levels of parathion and paraoxon were determined in mice at 19 days of gestation or Day 19 postpartum after administration of a single dose of 5 mg/kg parathion or 0.58 mg/kg paraoxon. Plasma (pseudo) cholinesterase activity was consistently lower in treated pregnant mice. Total brain cholinesterase was also suppressed to a greater degree in pregnant mice after treatment with parathion or paraoxon when compared with virgin animals treated similarly. In addition, when equal quantities of paraoxon (32 μg) were administered to both pregnant and virgin animals, total brain cholinesterase was significantly less in pregnant mice. Administration of parathion to lactating mice on Day 19 postpartum did not result in any significant differences in plasma or brain cholinesterase activity when compared to that in virgin animals. Pregnant mice treated with 5 mg/kg parathion demonstrated higher concentrations of both parathion and paraoxon in blood and brain than similarly treated virgin controls which correlated with the enhanced cholinesterase inhibition. Decreased ability to detoxify paraoxon was also demonstrated by a significant reduction in serum paraoxonase activity during pregnancy.

Influence of sex hormones on parathion toxicity in rats: antiacetylcholinesterase activity of parathion and paraoxon in plasma, erythrocytes, and brain.

Administration of parathion resulted in a greater inhibition of acetylcholinesterase (AChE) activity of plasma, erythrocytes, and brain in female rats than in male rats. No sex-related difference was observed in the antiacetylcholinesterase activity of paraoxon, an active metabolite of parathion. Gonadectomy increased the susceptibility of males but had no perceptible effect on females, resulting in comparable inhibition of AChE by parathion in both sexes. Administration of testosterone led to recovery from increased sensitivity to the antiacetylcholinesterase activity of parathion in castrated males and afforded partial protection to ovariectomized females. On the other hand, administration of estradiol further enhanced the enzyme inhibition by parathion in castrated males but had no significant effect on that in ovariectomized females. Alterations in the status of sex hormones did not affect the antiacetylcholinesterase activity of paraoxon in plasma and erythrocytes. However, inhibition of AChE activity by paraoxon was significantly higher in brains of gonadectomized rats than those of normal rats and the effect was reversible on administration of the respective sex hormones. The results indicate that testosterone plays an important role in determining parathion toxicity (as reflected by its antiacetylcholinesterase activity), probably by activating the oxidative cleavage of the insecticide into nontoxic metabolites.

Effect of some insecticides on cellular lipids of the neurosecretory complex of the red cotton bug,Dysdercus koenigii

In normal specimens of the bug,Dysdercus koenigii, the cells of the pars intercerebralis stain highly positively with Sudan black B and acid haematein, while the corpora cardiaca and allata stain lightly. After the administration of parathion, carbamate and endrin the situation is reversed. The increased level of lipids in the corpora cardiaca and allata coincides with the degree of loss of lipids from the cells of the pars intercerebralis.

Sulfur oxyacid production as a consequence of parathion desulfuration

Parathion desulfuration in vitro by the rat liver microsomal oxidase system gives rise to reactive sulfur atoms which either covalently bind to microsomal macromolecules, most likely as hydrodisulfides (-SSH) or appear as water-soluble metabolites. The latter were tentatively identified as sulfate, thiosulfate, and a minor amount of sulfite. Production of sulfate was enhanced by glutathione. Moreover, glutathione and other thiols removed covalently bound sulfur from the microsomal membranes and partially restored activity to enzymes known to be inactivated during parathion metabolism. A semilogarithmic plot of sulfur removal with time indicated at least two populations of covalently bound sulfur differing in the stability of the hydrodisulfide bond or accessibility to thiol compounds. The significance of transient hydrodisulfide formation with regard to the production of sulfur oxyacids is discussed. Both macromolecular and low molecular weight endogenous sulfhy dryl-containing biochemicals may play a role in preventing sulfur binding in vivo since only low level sulfur binding in liver homogenates was observed after the in vivo administration of parathion.

Enhancement of intestinal glucose transport following chronic parathion poisoning.

Chronic administration of parathion to male rats stimulated glucose (p less than 0.05) but not calcium (p greater than 0.05) transport in the everted duodenal gut sac preparation. Chronic parathion stimulation was not reduced by concurrent administered of atropine. Acutely applied parathion or paraoxon, its active metabolite, did not increase glucose transport in this preparation.

Deldrin and parathion interaction in the prostate and liver of the mouse.

The oral administration of dieldrin (1.25 mg/kg daily x 5 or 10) and/or parathion (5.2, 2.6, or 1.3 mg/kg daily x 5 or u0) caused significant alterations in the metabolism of [1,2-3H]testosterone by the anterior prostate gland and by the hepatic microsomal enzyme system in the mouse. A 5-day parathion treatment followed by another 5-day treatment with dieldrin led to significant increases in the levels of [3H]androstanediol a [3H]androstenedione formed by the prostate gland in vitro. Dieldrin alone, dieldrin plus parathion, or dieldrin administration followed by parathion treatment caused significant reductions in the levels of [3H]androstenedione formed by hepatic microsomal enzymes. Concomitantly, significant increases were observed in hepatic 7alpha-and 6beta-testosterone hydroxylase activities in animals treated with parathion followed by dieldrin administration. The present findings revealed that the administration of parathion or dieldrin leads to changes in the metabolism of male sex hormones in mouse liver and sex accessory organs. In addition, the simultaneous administration of parathion and dieldrin leads to an interaction that can alter the biologic effects of either compound.

Parathion administration in the monkey: Time course of inhibition and recovery of blood cholinesterases and visual discrimination performance

The effects of parathion [ O,O-diethyl O- p-nitrophenyl phosphorothionate] administration on activities of acetyl-cholinesterase (AChE) in blood and pseudocholinesterase (ChE) in plasma were studied in bonnet ( Macaca radiata) and rhesus ( M. mulatta) monkeys. In addition, the effects of parathion administration on performance of learned visual discrimination tasks were studied in rhesus monkeys. Peak inhibition of AChE and ChE occurred about 6 hr after administration of 0.5, 1.0, and 2.0 mg/kg parathion po. The degree of peak inhibition was greater for ChE than for AChE, was dose-related for both enzymes, and was of about the same magnitude in both species, even though control values for AChE and ChE differed in the two species. Activities of both enzymes returned to control values within 2 wk at all dose levels. Administration of 2.0, 1.5, and 1.0 mg/kg parathion abolished performance of the learned tasks 5 hr later and for as long as 3–7 days. When performance of the tasks returned after the 2.0 mg/kg dose, the level of performance remained below pretreatment values for up to 3 wk. A dose of 0.5 mg/kg did not affect performance. Comparison of the present findings with other work showed that reversal of blood AChE and ChE inhibition after parathion administration occurred more rapidly in monkey than in man but required more time in monkey than in mouse. It was observed that scopolamine and methyl scopolamine also blocked visual discrimination performance.