Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710
Received August 17, 1998; accepted April 30, 1999
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ABSTRACT |
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Key Words: Methyl parathion; acetylcholinesterase inhibition; organophosphorus insecticide; metabolic activation; cytochrome P450.
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INTRODUCTION |
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There are several data gaps regarding the risk assessment for methyl parathion in such areas, as to its pharmacokinetics and pharmacodynamics during pregnancy. The pharmacokinetic profile of organophosphorus insecticides is affected by factors such as route of administration (Carver and Riviere, 1989) and animal species (Qiao et al., 1994
). These insecticides are lipid-soluble and are capable of penetrating biological membranes, including the skin (Baynes and Bowen, 1995
; Carver and Riviere, 1989
; Draper and Street, 1981
; Nolan et al., 1984
; Wester et al., 1993
) and the placenta, and into the fetus (Salama et al., 1992 a
,b
; Villeneuve et al., 1972
). Physiological and biochemical changes associated with pregnancy may result in alterations in the pharmacokinetics of methyl parathion, with subsequent modifications of its pharmacodynamics and toxicity. During pregnancy, there is a reduction of several metabolism enzymes and xenobiotic-binding proteins that may influence the toxicity of methyl parathion. This insecticide undergoes metabolic activation and detoxification by: (a) hepatic and extrahepatic mirosomal cytochrome P450 (Chambers et al., 1991
; Hollingworth et al, 1967
; Nielsen et al., 1991
; Norman and Neal, 1976
; Sultatos, 1987
;), (b) esterases (Aldridge, 1953
), and (c) glutathione S-transferase (Hollingworth et al., 1973
). Pregnancy-induced suppression of these enzymes may change methyl parathion metabolism and disposition, resulting in its increased concentration in circulation and enhanced delivery to the maternal brain and the fetus. These events result in greater acetylcholinesterase inhibition and elevated cholinergic stimulation in both the mother and the fetus.
We report the results of an investigation into the pharmacokinetics, metabolism, and placental transfer of a single dermal 10.0 mg/kg (0.15 x LD50) of [14C]methyl parathion in pregnant Sprague-Dawley rats. Dermal application was used because it is a major route of entry for the test compound in residences, following indoor application.
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MATERIALS AND METHODS |
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Experimental animals.
Pregnant Sprague-Dawley rats (240350 g), at 1418 days of gestation, were purchased from Charles River Laboratories (Raleigh, NC). The animals were kept in a 12-h light/dark cycle (temperature 2123°C) and were provided with a free supply of feed (Rodent Laboratory Chow, Ralston Company, St. Louis, MO), as well as tap water. The animals were kept in plastic metabolism cages that allowed the separation of urine and feces.
Treatment of animals.
Radiolabeled and unlabeled methyl parathion were dissolved in acetone to obtain the desired specific radioactivity. A single dose of 10 mg (10 µCi)/kg in 0.1 ml acetone was applied with a micropipette to an unprotected 1 cm2 area of pre-clipped skin on the back of each animal's neck. The acetone was rapidly evaporated by gentle blowing. The dosage chosen was 15% of the dermal LD50, so that it would not produce maternal or fetal toxicity. Eight groups of 3 rats each were killed at time intervals of 1, 2, 4, 12, 24, 48, 72, and 96 h.
Animal handling.
After methyl parathion application, each rat was placed individually in a metabolism cage, and urine and feces were collected daily. At each time interval, the rats were anesthetized with an ip injection of sodium pentobarbital (50 mg/kg) and killed by heart exsanguination. Blood was collected via heart puncture with a heparinized syringe and centrifuged at 2400 rpm for 15 min at 5°C to separate red blood cells from plasma. Selected tissues (Table 1) were excised rapidly and stored at 70°C until analysis.
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Extraction of methyl parathion and metabolite.
Tissue samples (500 mg), plasma (0.1 ml), and urine (1 ml) were homogenized in 6 ml of a 1:1 mixture of n-hexane and ethyl acetate containing 1 ml of 0.1% phosphoric acid. Homogenates were centrifuged at 2500 rpm for 10 min and the organic layers were separated. The aqueous layer and precipitated protein were re-extracted with one additional volume of the solvent, and the organic layer was added to the original extract. The combined solvent extracts were concentrated by a gentle blowing of nitrogen. The residue was dissolved in 0.5 ml of n-hexane prior to HPLC analysis.
High performance liquid chromatography (HPLC).
The HPLC system used for analysis of methyl parathion and metabolites consisted of a Model 660 solvent programmer equipped with two Model 600A pumps, a Beckman 165 variable wavelength detector, a V-6k injector, and an RCM-100 radial compression separation system with C18 cartridge (Waters Associates, Inc., Milford, MA), a guard column filled with C18 µ Bondapack, and a Millipore Waters 740 Data Module. Millipore membrane filters, type HA or FH, pore size 0.45 mm (Millipore, Bedford, MA), were used to filter the solvents. Tissue and plasma extracts were injected in 10-µl volumes and eluted from the column by gradient elution. We used initial solvent (A) consisting of 38% water that contained 1 ml of 1% phosphoric acid and 62% methanol for 8 min, followed by solvent (B) consisting of 65% water that contained 1ml of 1% phosphoric acid and35% methanol for 15 min at a flow rate of 2 ml/min. The UV absorbance of the column elutes was monitored at 280 nm to detect and quantify methyl parathion and metabolites. A standard curve was obtained by injecting known amounts of each chemical and measuring the peak area. The retention time, peak areas, and percentage of each peak in the chromatogram were measured by the data processor.
Kinetic analysis.
The kinetic analysis of methyl parathion and metabolites in plasma and tissues were performed using a kalideograph for Macintosh program (Abou-Donia et al., 1983, 1995). The terminal half-life of methyl parathion and metabolites was calculated from the elimination rate constant, ß, that was obtained by linear regression of the terminal linear exponential decline in concentration, using the expression:
t =
The total area under the compound concentration vs. time curves for plasma, AUC plasma, and tissues, AUC organ, was calculated by the trapezoidal rule and extrapolated to infinity by using the last data point and the respective terminal linear experimental decline. The relative residence (RR) of methyl parathion in specific tissues with respect to plasma was calculated according to the equation:
RR =
where the AUC's are as defined above. Thus, the RR values reflect the relative accumulation of methyl parathion in specific organs or the relative exposure of individual organs to methyl parathion. The use of RR avoids the time-dependent changes in concentration ratios for various compounds with time.
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RESULTS |
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Recovery of Radioactivity
At the end of the 96-h experiment, the total radioactivity recovered from excreta, tissues, and application site was 98% of the applied dose. Radioactivity disappeared rapidly from the application site. The 14C content of the application site decreased biexponentially with time to 50% and 3% of the applied dose at one and 96 h, respectively. The apparent overall skin disappearance rate constants were 0.35 h1 and 0.03 h1 corresponding to half-lives of 2 h and 22 h, for the initial and terminal phase, respectively.
Radioactivity in Excreta
Radioactivity was rapidly excreted in urine. One h after application, 14% of the 14C was recovered in the urine. Urinary content of 14C reached a peak of 30% at 4 h. By the end of the 96-h experiment, a total of 91% of the applied dose was excreted in the urine. In contrast, only 3% of the administered dose was detected in the feces.
Tissue Distribution
Table 1 shows the concentration of radioactivity in plasma and various tissues at different time intervals after a single application of [14C]methyl parathion to pregnant rats. Radioactivity was extensively distributed in all tissues. The highest concentration of 14C was found in adipose tissue, followed by the kidney and liver. The nervous tissues from brain and spinal cord contained considerable concentrations of radioactivity, followed by the placenta and fetus.
Tissue Metabolism of Methyl Parathion
Qualitative and quantitative analyses of methyl parathion and metabolites were carried out using HPLC in plasma and tissues (Fig. 1). Methyl parathion was detected in all samples and accounted for most of the radioactivity throughout the experiment period (Table 2
). The maximum methyl parathion concentration in tissues exceeded those of plasma 496 h after dosing, suggesting that analyzed tissues have greater affinity for methyl parathion than to plasma components. The kidney and liver contained the highest concentrations of methyl parathion after one and two h of dosing. The fetus had the highest concentration 4 and 12 h after the administration. Methyl paraoxon was detected in the liver and brain (Table 3
), while p-nitrophenol was found only in the liver.
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DISCUSSION |
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Dermal application was carried out with unprotected skin. In this study, we attempted to approximate conditions of human exposure where the skin is usually naked or covered with loosely fitted clothing. Furthermore, the use of acclusive dressing results in the reversible hydration of the skin and leads to increased rates of absorption of many compounds, exaggerating the toxic effect caused by skin contact (Wurster and Kramer, 1961). Although the animals were housed individually, the possibility that some oral absorption might have occurred through grooming cannot be discounted. Sartorelli et al (1997) demonstrated the in vitro percutaneous penetration of methyl parathion through the human skin. Similar results were obtained in experimental animals for dermal application of other organophosphorus insecticides such as leptophos (O-methyl O-4-bromo-2,5-dichlorophenyl phenylphosphonothioate; Abou-Donia,1979
) and EPN (O-ethyl O-4-nitrophenyl phenylphosphonothioate; Abou-Donia et al.,1983
). Also, Knaak et al (1984) reported that 59% and 57% of dermally applied dose of parathion were absorbed through the skin of adult male and female rats, respectively. In the present study, methyl parathion was applied in 0.1-ml acetone. Since this solvent was rapidly evaporated by a gentle blowing, it is unlikely that it had a significant impact on the dermal absorption of the test compound. Although the rat is not a particularly good model of trans-dermal pharmacokinetics, it was used because a major aim of the study was the placental transfer that is usually investigated in pregnant rats.
The high solubility of methyl parathion in lipid solvents may explain its rapid absorption through the skin, considered to be by diffusion (Chang and Riviere, 1991; Scheuplein and Blank, 1971
). This suggestion is consistent with the finding that 91% of the dermally applied dose was excreted in the urine. It is also in agreement with the present finding that adipose tissue contained the highest concentration of radioactivity. Methyl parathion stored in adipose tissue may be released slowly into circulation, where it can be delivered to the nervous system and result in toxicity. Similar results were reported following oral administration of methyl parathion in rats (Garcia-Repetto et al., 1997
).
The kidney plays an important role in the excretion of methyl parathion and its metabolites as indicated by its high content of radioactivity. Nonionic absorption and passive re-absorption of methyl parathion in the renal tubule (Milne et al., 1958) are probably enhanced by the chemical's high lipid solubility. Similar results were reported for the ethyl analogue, parathion; a total of 85% of orally administered parathion to rats was recovered in urine, while more than 90% of the administered dose to pigs was detected in the urine (Nielsen et al, 1991
).
Methyl parathion analyzed by HPLC distributed rapidly in all tissues, with adipose tissue, liver, and kidney having the highest concentrations (Sultatos et al., 1990). Similar results were obtained with parathion following both intravenous injection (iv) and oral administration in dogs (De Schryver et al., 1987
), and after an iv injection in rabbits (Eigenberg et al., 1983
), and in pigs (Nielsen et al., 1991
). In this study, methyl parathion disappeared from the plasma, like that from other tissues, monoexponentially with a half-life of 11 h, similar to that of the fetus and kidney. Other tissues had longer half-life values with liver having the longest at 19.3 h, followed by placenta (16.5 h), and brain (13.6 h). The elimination half-life in dogs was 7.2 h for an iv injection of methyl parathion (Brackman et al., 1983
) and 9.7 min for an ip injection of methyl paraoxon (De Schryver et al., 1987
). In the present study, methyl parathion and metabolites were analyzed in the extracts of total fetal homogenates. It is realized, however, that methyl parathion concentrations in individual fetal tissues such as the brain may vary from the total compartment, but these data were not available.
Methyl parathion undergoes metabolic biotransformation by hepatic and extrahepatic phase I and phase II metabolism. Phase I reactions include methyl parathion desulfuration by cytochrome P450 (Norman and Neal, 1976; Norman et al., 1973
; Sultatos and Murphy, 1983
). Butler and Murray (1997) have recently shown the major involvement of CYP3A4 ioszyme in the desulfuration of parathion. This reaction results in the formation of methyl paraoxon, the only active metabolite that is a more potent compound (Yamamoto et al., 1983
; Zhang and Sultatos, 1991
). Cytochrome P450 also catalyzes de-arylation of methyl parathion to p-nitrophenol and dimethyl phosphorothioic acid (Neal, 1967
). The third phase I reaction is the hydrolysis of paraoxon by liver and plasma paraoxanase (Tyndall and Daniel, 1975
). Phase II reactions include: (a) conjugation of methyl parathion with glutathione by glutathione S-aryl transferase to form p-nitrophenyl mercapturic acid (Hollingworth et al., 1973
; Huang and Sultatos, 1993
) and glutathione S-akyl transferase to yield S-methyl glutathione (Abou-Donia, 1994
; Radulovic and Kulkarni, 1987
), b) p-nitrophenol is further conjugated with glucuronic acid and sulfuric acid (Neale and Parke, 1973
).
Figure 3 presents a suggested scheme for the metabolism of a single dermal application of [14C]methyl parathion in pregnant rats. Methyl parathion was detected in all analyzed tissues, while methyl paraoxon was found in the liver and brain and p-nitrophenol was detected only in the liver. Methyl paraoxon had a longer half-life in the liver than that of its parent compound. The RR values of methyl parathion in various tissues relative to plasma reflect its accumulation and persistence, as well as its relative pool size, in these tissues when compared to plasma. Both kidney and liver had high RR values, reflecting their role in elimination of this insecticide. Fetal tissue had a higher RR value, while placenta exhibited the highest RR value of all tissues, suggesting that this tissue functions as a temporary depot for methyl parathion in the animal's body. As time passes, methyl parathion is released from this storage tissue, mobilized and transferred into the fetus. The high RR values in placental and fetal tissues suggest that the fetus is vulnerable to methyl parathion toxicity following exposure to toxic levels. Similar patterns of disposition in pregnant rats were reported for methamidophos (O,S-dimethyl phosphoroamidothioate; Salama et al., 1992a
), acephate (O,S-dimethyl acetylphosphoroamidothioate; Salama et al., 1992b
) and chrolpyrifos (O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphosphorothioate; Abdel-Rahaman et al., 1993
).
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NOTES |
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2 To whom correspondence should be addressed at Department of Pharmacology and Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, NC 27710. Fax: (919) 681-8224. E-mail: donia{at}acpub.duke.edu.
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