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PubMed1993

Inhibition and inactivation of constitutive cytochromes P450 in rat liver by parathion.

Phosphorothioate pesticides, such as parathion (O,O-diethyl-O-4-nitrophenyl phosphorothioate), undergo enzymic oxidation to the active insecticidal agents that are the analogous organophosphorus compounds. In hepatic microsomal fractions, the NADPH-mediated conversion of parathion to paraoxon occurs with concomitant loss of cytochrome P450 (P450) and associated activities. In this study, the capacity of parathion to inactivate specific P450 enzymes was studied in rat hepatic microsomes. Parathion was a potent inhibitor of P450 3A2- and 2C11-mediated androst-4-ene-3,17-dione (androstenedione) 6 beta- and 16 alpha-hydroxylation (Ki values of 13 +/- 2 and 2.3 +/- 0.1 microM, respectively, and Km/Ki ratios of 1.4 +/- 0.2 and 11 +/- 1, respectively). After a 10-min preincubation between parathion and NADPH-supplemented microsomes, to inactivate P450 before androstenedione hydroxylation was carried out, the corresponding Km/Ki ratios were increased to 3.5 +/- 0.4 and 35 +/- 6, reflecting 2.5- and 3.2-fold enhancement of inhibition of P450 3A2- and 2C11-dependent activities. In contrast to these findings, P450 2A1/2-mediated androstenedione 7 alpha-hydroxylation was refractory to inhibition and P450 2C6-mediated progesterone 21-hydroxylation was inhibited but not inactivated by the pesticide. Further studies established that androstenedione 6 beta- and 16 alpha-hydroxylation pathways were inactivated with maximal half-times of 2.59 min and 1.72 min, respectively. Although the incubation of parathion (50 microM) with rat liver microsomes for 10 min led to a 16% decrease in P450 estimated spectrophotometrically, immunoblot analysis revealed no change in the microsomal content of P450 2C11 apoprotein. Finally, NADPH-mediated metabolism of parathion to paraoxon (by desulfuration) and 4-nitrophenol (by oxidative cleavage of the phosphorothioate ester) occurred efficiently in microsomes (4.32 and 4.35 nmol/min/mg of protein, respectively). P450 loss was estimated under the same incubation conditions and, thus, 210 parathion molecules were oxidized for each molecule of holo-P450 lost. These findings establish that parathion is a potent inhibitor and inactivator of the principal constitutive P450s, 3A2 and 2C11, in rat liver, whereas the P450s 2A1 and 2A2 are refractory to either inhibition or inactivation. Another major constitutive enzyme, P450 2C6, is inhibited effectively by parathion but does not appear to be subject to inactivation.

Androstenedione↗
PubMed1987

Biotransformation of methyl parathion by human foetal liver glutathione S-transferases: an in vitro study.

The role of human foetal liver glutathione S-transferases in the detoxification of methyl parathion was investigated. Glutathione S-transferases were partially purified by affinity chromatography utilizing reduced glutathione as the ligand coupled to epoxy-activated Sepharose 4B. This resulted in the isolation of material with an average activity (mean +/- S.E.) of 58.90 +/- 4.83 mumol 1-chloro-2,4-dinitrobenzene conjugate formed/min per mg, representing a purification of 70-fold. These partially purified foetal liver transferases catalysed the metabolism of methyl parathion exclusively to desmethyl parathion via O-dealkylation. High-performance liquid chromatography, radiometric analysis of the enzymic reaction, and co-chromatography with reference standard on thin-layer chromatography confirmed the sole metabolite as desmethyl parathion. The range of foetal liver activity towards methyl parathion was from 30 to 122 nmol desmethyl parathion formed/min per mg. Analysis of the kinetic parameters of three partially purified foetal liver preparations with gestational ages of 14, 16 and 21 weeks resulted in Km values for methyl parathion of 0.24, 0.38 and 0.86 mM, respectively; whereas, the Km values assessed for glutathione were 0.20, 0.10 and 0.18 mM. The ability of human foetal liver glutathione S-transferases to catalyse the metabolism of methyl parathion exclusively to desmethyl parathion via O-dealkylation represents a major qualitative biochemical difference from the rat-liver isozymes.

Biotransformation↗
PubMed1979

Accelerated parathion degradation in soil inoculated with acclimated bacteria under field conditions.

The feasibility of decontaminating soil at parathion spillage or disposal sites by inoculation with a highly acclimated culture of parathion-degrading bacteria was demonstrated under in situ field conditions. The acclimated culture (AC), capable of utilizing parathion as a sole carbon and energy source, was inoculated into Yolo silt loam soil in which parathion was applied at rates up to 5000 kg/ha. The AC was shown to be capable of completely degrading parathion in soil containing up to 1250 kg/ha of parathion within 35 days. A slower rate of parathion degradation by the AC was observed when the pesticide was applied as the commercial 46.5% emulsifiable concentrate than when applied as the 98% technical grade. The ability of the AC to degrade parathion deteriorated at application rates greater than 1250 kg/ha. The AC may have been adversely affected by the accumulation of the parathion hydrolytic products, p-nitrophenol and ionic diethyl thiophosphate, which were tentatively identified in soil samples.

Biodegradation, Environmental↗
PubMed2006

Kinetics and mechanism of the degradation of methyl parathion in aqueous hydrogen sulfide solution: investigation of natural organic matter effects.

The kinetics of the transformation of methyl parathion have been investigated in aqueous solution containing reduced sulfur species and small concentrations of natural organic matter (NOM) from different sources such as soil, river, and peat. It was shown that NOM mediates the degradation of methyl parathion in aqueous solutions containing hydrogen sulfide. After evaluating and quantifying the effect of the NOM concentration on the degradation kinetics of methyl parathion in the presence of hydrogen sulfide, it was found that the observed pseudo-first-order reaction rate constants (k(obs)) were proportional to NOM concentrations. The influence of pH on the degradation of methyl parathion in the aqueous solutions containing hydrogen sulfide and NOM has been studied. The rate of degradation of methyl parathion was strongly pH dependent. The results indicate k(obs) with a commercially available humic acid has a maximum value at approximately pH 8.3. Two main reaction mechanisms are identified to dominate the degradation of methyl parathion in aqueous solution containing hydrogen sulfide and NOM based on the products aminomethyl parathion and desmethyl methyl parathion. The two mechanisms are nitro-group reduction and nucleophilic attack at the methoxy-carbon. The reduction of the nitro-group is only observed in the presence of NOM. The results of this study form an important base for the evaluation and interpretation of transformation processes of methyl parathion in the environment.

Humic Substances↗
PubMed1967

Studies of the enzymic mechanism of the metabolism of diethyl 4-nitrophenyl phosphorothionate (parathion) by rat liver microsomes.

1. The metabolism of parathion by rat liver microsomes is affected by various enzyme inhibitors in a manner quite typical of the ;mixed-function oxidase' enzyme systems. 2. With many of these inhibitors (p-chloromercuribenzoate, Cu(2+), 8-hydroxyquinoline) the conversion of parathion into diethyl hydrogen phosphorothionate is less inhibited than conversion into diethyl 4-nitrophenyl phosphate (paraoxon). 3. Compounds containing reduced sulphur stimulate the overall metabolism of parathion. However, the conversion of parathion into diethyl hydrogen phosphorothionate is stimulated more than its conversion into paraoxon. 4. The metabolism of parathion to diethyl hydrogen phosphorothionate is also stimulated by EDTA, Ca(2+) and Ba(2+), but these stimulatory effects are not additive. 5. The electron acceptors FAD, riboflavine, menadione and methylene blue exhibit a concentration-dependent differential inhibition of the metabolism of parathion to diethyl hydrogen phosphorothionate and to paraoxon. 6. The concentration of parathion required for the half-maximal rate of production of diethyl hydrogen phosphorothionate is significantly different from the concentration required for half-maximal rate of production of paraoxon. 7. The results are discussed in terms of either two separate enzyme systems metabolizing parathion to diethyl hydrogen phosphorothionate and to paraoxon or two different binding sites for parathion, which share a common electron-transport pathway.

Animals↗
PubMed2000

Placental transfer and pharmacokinetics of a single dermal dose of [14C]methyl parathion in rats.

The pharmacokinetics and placental transfer of a single dermal 10.0 mg (10microCi)/kg dose of uniformly phenyl-labeled [14C] methyl parathion (0,0-dimethyl 0-4-nitrophenyl phosphorothioate) were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three rats were killed at each time interval: 1, 2, 4, 12, 24, 48, 72, and 96 h after dosing. Radioactivity disappeared biexponentially from the administration sites, which retained 50% and 3% of the dose after 1 h and 96 h, respectively. Most of the absorbed radioactivity was excreted in the urine (91%). Only 3% of the 14C was recovered in the feces. One h after the administration, radioactivity was detected in all tissues, including fetal tissue. The peak maternal plasma concentration of radioactivity (ng methyl parathion equivalent/ml) was 1005 at 2 h, compared to 318 ng for fetal plasma at 12 h. The maximum concentrations of radioactivity (ng methyl parathion equivalent/g), detected in most tissues within 12 h of dosing, were, in descending order: adipose tissue (67,532), kidney (1,571), spleen (1,256), spinal cord (1,004), heart (729), liver (706), brain (546), placenta (389), and fetus (256). The metabolism studies showed that methyl parathion, detected by HPLC, was the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 513 ng/ml, and in the following tissues (ng/g fresh tissue): kidney (819), fetus (668), placenta (394), liver (375), and brain (282). The metabolite methyl paraoxon was detected in maternal brain and liver at maximum concentrations (ng/g fresh tissue) of 135 and 64 after 12 h and 4 h respectively, while p-nitrophenol was only detected in liver at a maximum concentration of 21 ng/g 72 h after dosing. Pharmacokinetic studies showed that methyl parathion disappeared monoexponentially from plasma and tissues. The half-life of elimination of methyl parathion from plasma was 11 h corresponding to a constant rate value of 0.06 h(-1). The results indicate that skin and placenta are poor barriers against methyl parathion permeability, resulting in a rapid and extensive dermal absorption of this insecticide and extensive placental transfer. This is indicated by the relative residence (R(R)) of methyl parathion in the plasma, which was largest in the placenta followed by the fetus. This study suggests that pregnant women and fetuses may be at risk of cholinergic toxicity following dermal exposure to methyl parathion.

Administration, Cutaneous↗
PubMed1995

Identification of a reversible component in the in vitro inhibition of rat hepatic cytochrome P450 2B1 by parathion.

Cytochrome P450 (P450) enzymes are inactivated in suicidal fashion during microsomal parathion oxidation. In the present study, two distinct components of the inhibition of the phenobarbital (PB)-inducible P450 2B1 by parathion were characterized. Here we report for the first time that low concentrations of parathion potently and reversibly inhibited, but did not inactivate, 2B1. In contrast, the previously described inactivation process occurred only at considerably higher parathion concentrations, at which concentrations enzyme activity was already extensively inhibited. At low concentration, parathion was a competitive inhibitor of 2B1-mediated androstenedione 16 beta-hydroxylation (Ki = 0.44 +/- 0.07 microM) and of 7-pentylresorufin O-depentylation (Ki = 0.40 +/- 0.03 microM) in microsomes from PB-pretreated rats and was similarly effective against androstenedione 16 alpha- and 16 beta-hydroxylation catalyzed by purified 2B1. Although preincubation of higher concentrations of parathion (> 5 microM) with NADPH-supplemented microsomes from PB-pretreated rat liver decreased holo-P450, heme loss was not observed near the Ki values. Instead, half-maximal loss of P450 occurred at 6 microM and at 9 microM parathion in PB-pretreated microsomes and in the reconstituted system, respectively. Parathion metabolism was efficient in PB-microsomes (Km values for 4-nitrophenol and paraoxon formation were 13 microM and 10 microM, respectively) and in the reconstituted system (corresponding Km values were 19 microM and 14 microM). Thus the constants for P450 inactivation and for parathion metabolism were similar and were at least 15-fold greater than the Ki values for the reversible process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Effects of enzyme inducers or inhibitors on the pharmacokinetics of intravenous parathion in rats.

In order to find what form of hepatic cytochrome P450 (CYP) is involved in the metabolism of parathion to form paraoxon, rats were pretreated with the enzyme inhibitors, such as SKF 525-A and ketoconazole or enzyme inducers, such as dexamethasone, isoniazid, phenobarbital, and 3-methylcholanthrene. Parathion, 3 mg/kg, was infused in 1 min via the jugular vein. In rats pretreated with SKF 525-A or ketoconazole, nonspecific CYP inhibitors, the area under the plasma concentration-time curve from time zero to time infinity (AUC) and total body clearance (Cl) of parathion were significantly greater and slower, respectively, than those in respective control rats, suggesting that parathion was metabolized by CYPs. In rats pretreated with dexamethasone (CYP3A23 inducer), the AUC was significantly smaller (41.5 compared with 52.5 microg min/mL), Cl was significantly faster (72.2 compared with 57.1 mL/min/kg), and the amounts and/or tissue-to-plasma ratios of parathion was significantly (or tended to be) smaller than those in control rats. However, the pharmacokinetic parameters of parathion were not significantly different after pretreatment with other enzyme inducers compared with respective control rats. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible CYP3A23, the induction of which was confirmed by Western blot analysis. This was supported by in vitro intrinsic clearance (Cl(int)) of parathion to form paraoxon in hepatic microsomal fraction; the Cl(int) in rats pretreated with dexamethasone was significantly faster (0.0900 compared with 0.0290 mL/min/mg protein) than that in control rats.

Animals↗
PubMed1991

Investigation of a fatality among parathion applicators in California.

Staff of the California Department of Health Services investigated the death of a parathion applicator in California that was thought to be pesticide-related. A crew of eleven workers (including six sprayers, three mixer/loaders, one mixer/sprayer and one foreman) had been applying 0.125% parathion spray to almond orchards for approximately three weeks. On the day of the fatality, a sprayer rapidly developed symptoms of salivation, sweating, and convulsions after a half-day of work. Despite aggressive medical treatment, the worker died within one hour of his initial symptoms. Significant laboratory results for the decreased case included: parathion residue on the inner and outer garments worn by the worker, parathion in the post-mortem gastric contents, and elevated urinary metabolites consistent with acute parathion intoxication. Interviews with the work crew revealed that three of the 10 workers had complaints of headaches, vomiting, and/or sore throat; yet, subsequent plasma and red cell cholinesterase tests of the co-workers did not show any significant depressions in comparison with pre-season baseline values. This worker death is consistent with prior reports of parathion-related sprayer/applicator intoxications and is the first worker-related parathion death in California since 1972. Substitution of pesticides with less toxic active ingredients or the elimination of parathion is recommended.

Adult↗
PubMedDate not supplied

A comparison of cholinesterase activity after intravenous, oral or dermal administration of methyl parathion.

Time-dependent changes in blood cholinesterase activity caused by single intravenous, oral or dermal administration of methyl parathion to adult female rats were defined. Intravenous and oral administration of 2.5 mg/kg methyl parathion resulted in rapid (<60 min) decreases in cholinesterase activity which recovered fully in vivo within 30-48 h. In contrast, spontaneous reactivation of cholinesterase in vitro was complete within 6 h at 37 degrees C. Dermal administration of methyl parathion caused dose-dependent inhibition of cholinesterase activity which developed slowly (> or =6 h) and was prolonged (> or =48 h). Time- and route-dependent effects of methyl parathion on cholinesterase activity in brain and other tissues generally paralleled its effects on activity in blood. In conclusion, pharmacodynamics of methyl parathion differ substantially with route of exposure. Recovery of cholinesterase in vivo after intravenous or oral exposure may partially reflect spontaneous reactivation and suggests a rapid clearance of methyl parathion or its active metabolite methyl paraoxon. The more gradual and prolonged inhibition of cholinesterase caused by dermal administration is consistent with disposition of methyl parathion at a site from which it or methyl paraoxon is only slowly distributed. Thus, dermal exposure to methyl parathion may pose the greatest risk for long-term adverse effects.

Administration, Cutaneous↗
PubMedDate not supplied

Pharmacokinetics of methyl parathion: a comparison following single intravenous, oral or dermal administration.

Assessment of the risks posed by the residential use of methyl parathion requires an understanding of its pharmacokinetics after different routes of exposure. Thus, studies were performed using adult female rats to define the pharmacokinetic parameters for methyl parathion after intravenous injection and to apply the described model to an examination of its pharmacokinetics after single oral or dermal exposure. The pharmacokinetics of methyl parathion after intravenous administration (1.5 mg/kg) were best described by a three-compartment model; the apparent volume of the central compartment was 1.45 liters/kg, clearance was 1.85 liters/h/kg and the terminal half-life was 6.6 h with an elimination constant of 0.50 h(-1). The apparent oral absorption coefficient for methyl parathion (1.5 mg/kg) was 1.24 h(-1), and its oral bioavailability was approximately 20%. The latter likely includes a significant first pass effect. Concentrations of methyl parathion increased during the initial 10-60 min and then declined during the next 15-36 h. After dermal administration (6.25-25 mg/kg), methyl parathion concentrations peaked within 12-26 h and then declined dose dependently. The apparent dermal absorption coefficient was approximately 0.41 h(-1), and only two pharmacokinetic compartments could be distinguished. In conclusion, the pharmacokinetics of methyl parathion are complex and route dependent. Also, dermal exposure, because of sustained methyl parathion concentrations, may pose the greatest risk.

Administration, Cutaneous↗
PubMed2002

Electrochemical detection of parathion at a glassy-carbon electrode modified with hexadecane.

A modified electrode, based on a hexadecane (C(16))-coated glassy-carbon electrode (GCE) has been developed for the determination of parathion. The electrochemical behavior of parathion was investigated by cyclic voltammetry (CV). The peak potential and peak current were found to depend on the supporting electrolyte and the pH of the buffer solution. The reduction currents for parathion were proportional to parathion concentration over the range 8x10(-8)-2x10(-5) mol L(-1). The detection limit was 2x10(-8) mol L(-1) parathion for an accumulation time of 30 s. The effects of organic and inorganic species on the determination of parathion were also studied. A procedure was developed to extract parathion from spiked soil samples using a mixture of dichloromethane and acetone as the extraction solvent. The complete extraction and analytical procedure are simple, inexpensive and rapid. Parathion was determined in a soil sample by use of linear scan voltammetry (LSV).

Alkanes↗
PubMed2005

A novel amperometric sensor and chromatographic detector for determination of parathion.

A novel amperometric sensor and chromatographic detector for determination of parathion has been fabricated from a multi-wall carbon nano-tube (MWCNT)/Nafion film-modified glassy-carbon electrode (GCE). The electrochemical response to parathion at the MWCNT/Nafion film electrode was investigated by cyclic voltammetry and linear sweep voltammetry. The redox current of parathion at the MWCNT/Nafion film electrode was significantly higher than that at the bare GCE, the MWCNT-modified GCE, and the Nafion-modified GCE. The results indicated that the MWCNT/Nafion film had an efficient electrocatalytic effect on the electrochemical response to parathion. The peak current was proportional to the concentration of parathion in the range 5.0x10(-9)-2.0x10(-5) mol L(-1). The detection limit was 1.0x10(-9) mol L(-1) (after 120 s accumulation). In high-performance liquid chromatography with electrochemical detection (HPLC-ED) a stable and sensitive current response was obtained for parathion at the MWCNT/Nafion film electrode. The linear range for parathion was over four orders of magnitude and the detection limit was 6.0x10(-9) mol L(-1). Application of the method for determination of parathion in rice was satisfactory.

Biosensing Techniques↗
PubMed1994

Effects of parathion on membrane organization and its implications for the mechanisms of toxicity.

The effects of the organophosphorus insecticide parathion (O,O-diethyl O-(p-nitrophenyl)phosphorothioate) on the physical state of synthetic and native membranes was investigated by fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH), probing the bilayer core, and by its anionic propionic acid derivative (DPH-PA), probing the outer regions of the bilayer. Parathion disorders the gel phase of liposomes reconstituted with dimyristoylphosphatidylcholine (DMPC), broadening the transition profile and shifting the temperature midpoint of the phase transition, as detected by both probes. The insecticide strongly orders the fluid phase either in the hydrophobic core or in the outer regions of the membrane, as evaluated by DPH and DPH-PA, respectively. These ordering effects of parathion were further confirmed in fluid models of egg-yolk phosphatidylcholine. Parathion increases to some extent the ordering promoted by cholesterol in DMPC bilayers, but high cholesterol concentrations (> or = 30 mol%) prevent parathion interaction. The results in native membranes correlate reasonably with those obtained in models of synthetic lipids. Thus, parathion does not exert detectable effects in cholesterol-rich membranes, namely, erythrocytes, but moderate ordering effects of parathion are detected by both probes in brain microsomes, i.e., membranes with a lower content of cholesterol. Again, in agreement with the models of synthetic lipids, pronounced ordering effects of parathion are detected in cholesterol-poor membranes, e.g., sarcoplasmic reticulum and mitochondria.

Animals↗
PubMed1983

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 micrograms) 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.

Animals↗
PubMed1984

Percutaneous absorption and dermal dose-cholinesterase response studies with parathion and carbaryl in the rat.

Dermal dose-ChE response (toxicity) and percutaneous absorption of parathion and carbaryl were studied in the rat. Parathion was as toxic to young animals as it was to adults of the same sex and more toxic to adult females than to adult males. Carbaryl was nontoxic at administered dosages. In each percutaneous absorption study, [14C]parathion or [14C]carbaryl was applied to back skin (12.5-13.8 cm2) at 43.5 to 48 micrograms/cm2. Thirty-six rats were treated and three were killed at time intervals between 0.5 and 168 hr. The area of the skin which had been treated, plasma, heart, liver, kidneys, urine, feces, and the remaining carcass were analyzed for 14C. Recovery studies indicated that adult male and female rats, respectively, absorbed 59.2 and 57.0% of the applied parathion, while adult males absorbed 57.7% of the applied carbaryl. Parathion was lost from skin (t1/2, 28.6 hr) more rapidly than carbaryl (t1/2, 40.6 hr). Approximately 1.4 and 5.8%, respectively, of the applied parathion and carbaryl penetrated the skin within 1 hr and was available for absorption. Parathion was absorbed through skin of adult male and female rats, respectively, at rates of 0.33 and 0.49 micrograms hr-1 cm-2. Carbaryl was absorbed by male rats at the rate of 0.18 micrograms hr-1 cm-2. The half-lives for absorption of parathion by blood ranged between 0.38 and 2.1 hr, while elimination half-lives ranged between 28.6 and 39.5 hr. Carbaryl absorption and elimination half-lives were 1.26 and 67 hr, respectively.

Animals↗
PubMed1998

The actions of the H2-blocker cimetidine on the toxicity and biotransformation of the phosphorothioate insecticide parathion.

Parathion, like most organophosphorus insecticides currently in use, must undergo cytochrome P450(P450)-dependent activation in order to exert its acute mammalian toxicity (cholinergic crisis). Since P450 isoforms play such an important role in mediating the toxicity of parathion and related insecticides, factors which significantly alter P450 activities, such as exposure to certain xenobiotics, can also be expected to affect the toxicity of these potentially hazardous insecticides. Cimetidine is a H2-histamine antagonist that has been shown to inhibit several P450-isoforms. In addition, administration of cimetidine has been reported to result in clinically significant pharmacokinetic interactions with a wide variety of drugs. In the present study coexposure to cimetidine and parathion resulted in a moderate increase in the toxicity of this pesticide. However, coexposure to cimetidine and paraoxon did not alter the toxicity of the organophosphate, indicating that cimetidine likely affected P450-dependent formation of paraoxon from parathion. In vitro incubations of mouse hepatic microsomes demonstrated that, in addition to reducing the velocity of P450-dependent metabolism of parathion, cimetidine increased the proportion of paraoxon formed (activation). and decreased the proportion of p-nitrophenol formed (detoxification). Since parathion is not eliminated significantly by other routes in the mouse, the bulk of parathion in vivo was metabolized by P450 (although more slowly) in the presence of cimetidine, leading to a greater amount of paraoxon produced, and therefore greater toxicity. Incubations with individual P450 isoforms suggested that cimetidine could act by inhibition of P450 isoforms that detoxify parathion to a greater degree than cimetidine-resistant isoforms, and/or cimetidine could alter the proportions of detoxification versus activation of certain individual isoforms.

Animals↗
PubMed2001

Absorption, distribution, metabolism and excretion of daily oral doses of [14C]methyl parathion in hens.

Adult hens were given oral daily doses of 2 mg (2 microC(i))/kg/day (14% of oral LD(50) in male rats) of [14C]methyl parathion (O,O-dimethyl O-4-nitrophenyl phosphorothioate) for 10 consecutive days. Five treated hens were sacrificed at 1, 2, 4, 8, 12, 24, and 48 h after the last dose. Methyl parathion was absorbed from the gastrointestinal tract and distributed rapidly. Maximum radioactivity was detected in tissues within 8 h of dosing, (ng methyl parathion equivalent/g fresh tissue or ml plasma): Plasma (189.2), liver (94.7), kidney (146.2), brain (61.4), gastrointestinal tissues (106.7). Methyl parathion was detected in the plasma, kidney and liver, while methyl parathion metabolite p-nitrophenol was detected in the liver and in the kidney. Elimination of methyl parathion from plasma was monophasic with a terminal half-life of 17.5 h, corresponding to an elimination rate constant of 0.039 ng/hr. Most of the absorbed radioactivity was excreted in the combined fecal-urine excreta (98%). Analysis of the metabolites in the excreta revealed that non-conjugated metabolites accounted for 13% of the total excretion. Conjugated metabolites accounted for 87% of the total excretion; of that, 6% as p-nitrophenyl-glucoronide conjugate, 7% as p-nitrophenyl-sulfate conjugate, 23% as bound hot sulfuric acid hydrolyzable residues, and 51% as water soluble metabolites. The presence of majority of radioactivity in the excreta as conjugated metabolites indicates that determining only unbound p-nitrophenol as a biological marker for methyl parathion exposure underestimates total fecal-urine excretion of p-nitrophenol. The slow elimination rate of methyl parathion is significant, since hens are more comparable to humans with respect to their cytochrome P450 activities.

Absorption↗