Methyl parathion metabolism

Hollingworth RM, Metcalf RL, Fukuto IR. 1967. The selectivity of sumithion compared with methyl parathion. Metabolism in the white mouse. J Agric Food Chem 15 242-249. 

Levels of Significant Exposure to Methyl Parathion - Inhalation 3-2. Levels of Significant Exposure to Methyl Parathion - Oral 3-3. Proposed Metabolic Pathways of Methyl Parathion... 

Results of methyl parathion assays involving effects on chromosomes have also been contradictory. For sister chromatid exchange, Waters et al. (1982) reported a positive response in Chinese hamster ovary cells only in the presence of metabolic activation system, while methyl parathion tested positive without a metabolic activation system in Chinese hamster V79 cells (Chen et al. 1981), cultured normal human lymphoid cells (Chen et al. 1981 Gomez-Arroyo et al. 1987 Sobti et al. 1982), and Burkitt s l5miphoma cells (Chen et al. 1981). Chen et al. (1981) found a significant dose-related increase in sister chromatid exchange in both hamster and human cultured cells, but dose-related cell cycle delays were less pronounced in human cell lines than in V79 cells. Negative results were obtained for chromosomal aberrations in human lymphocytes without a metabolic activation system (Kumar et al. 1993). 

Figure 3-3. Proposed Metabolic Pathways of Methyl Parathion... 

Data from a single study in dogs suggest that hepatic first-pass metabolism may limit systemic availability of the parent compound following oral exposure (Braeckman et al. 1983). Placental transfer of methyl parathion was demonstrated in pregnant rats 1-3 days before parturition. Thirty minutes after administration, both methyl parathion and methyl paraoxon were found in fetal brain, liver, and muscle methyl parathion, but not methyl paraoxon, was detected in placenta and maternal liver (Ackermann and Engst 1970). Methyl parathion binds reversibly to serum albumin, but is readily distributed to the tissues (Braeckman et al. 1980, 1983). 

It is not presently known what phase I enzymes metabolize methyl parathion, and consequently, whether metabolism differs between children and human adults. There is some suggestive evidence for age-related differences in metabolism of methyl parathion in rats (Benke and Murphy 1975). 

These results are supported by studies in animals in which methyl parathion was detected 30-155 minutes after exposure (oral, dermal, inhalation, or intravenous routes) in plasma and liver (Abu-Qare et al. 2000 EPA 1978e). Due to extensive and rapid metabolism of methyl parathion (see Section 3.3), measurable levels are not expected to persist in tissue or serum for prolonged periods after exposure. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Permethrin, a pyrethrin pesticide, decreased the inhibition of brain cholinesterase activity by methyl parathion, but methyl parathion decreased the LD50 of permethrin when the two pesticides were simultaneously administered to rats (Ortiz et al. 1995). The potentiation of permethrin lethality may be due to the inhibition by methyl parathion of carboxylesterase, which metabolizes permethrin. 

Absorption, Distribution, Metabolism, and Excretion. Evidence of absorption comes from the occurrence of toxic effects following exposure to methyl parathion by all three routes (Fazekas 1971 Miyamoto et al. 1963b Nemec et al. 1968 Skiimer and Kilgore 1982b). These data indicate that the compound is absorbed by both humans and animals. No information is available to assess the relative rates and extent of absorption following inhalation and dermal exposure in humans or inhalation in animals. A dermal study in rats indicates that methyl parathion is rapidly absorbed through the skin (Abu-Qare et al. 2000). Additional data further indicate that methyl parathion is absorbed extensively and rapidly in humans and animals via oral and dermal routes of exposure (Braeckman et al. 1983 Flollingworth et al. 1967 Ware et al. 1973). However, additional toxicokinetic studies are needed to elucidate or further examine the efficiency and kinetics of absorption by all three exposure routes. 

The available information in humans regarding the metabolism of methyl parathion is limited to in vitro studies (Hollingworth et al. 1973). However, the in vitro (Benke and Murphy 1975 Benke et al. 1974 Hollingworth et al. 1973 Nakatsugawa et al. 1968 Neal and DuBois 1965) metabolic pathway of this chemical has been characterized in animals. 

Practically all toxicokinetic properties reported are based on the results from acute exposure studies. Generally, no information was available regarding intermediate or chronic exposure to methyl parathion. Because methyl parathion is an enzyme inhibitor, the kinetics of metabolism during chronic exposure could differ from those seen during acute exposure. Similarly, excretion kinetics may differ with time. Thus, additional studies on the distribution, metabolism, and excretion of methyl parathion and its toxic metabolite, methyl paraoxon, during intermediate and chronic exposure are needed to assess the potential for toxicity following longer-duration exposures. 

BCF factors in fish ranging from 1.08 to 1.85, indicating that bioconcentration of methyl parathion is not an important fate process (Crossland and Bennett 1984). In another study, methyl parathion was added to the water of a carp-rearing pond and the concentration of methyl parathion was measured in water, soil, macrophytes, and carp over a 35-day period. Results showed that methyl parathion accumulated in macrophytes for 1 day and in carp for 3 days following exposure, and then dissipated. The concentrations of methyl parathion decreased in macrophytes by 94% by day 35 and by 98% in carp tissue by day 28 (Sabharwal and Belsare 1986). These data indicate the potential for biomagnification in the food chain is likely to be low because methyl parathion appears to be metabolized in aquatic organisms. 

Exposure Levels in Humans. Methyl parathion has been detected in serum and tissue shortly after acute exposure (EPA 1978e Ware et al. 1975). It is rapidly metabolized and does not persist in serum and tissues for long (Braeckman et al. 1983). Two metabolites of methyl parathion, 4-nitrophenol and dimethyl phosphate, can be detected in urine and tissues for up to 2 days following exposure (Morgan et al. 1977). These compounds are specific for methyl parathion when there is a history of exposure. 

In a study of the metabolism of methyl parathion in intact and subcellular fractions of isolated rat hepatocytes, a high performance liquid chromatography (HPLC) method has been developed that separates and quantitates methyl parathion and six of its hepatic biotransformation products (Anderson et al. 1992). The six biotransformation products identified are methyl paraoxon, desmethyl parathion, desmethyl paraoxon, 4-nitrophenol, />nitrophenyl glucuronide, and /wiitrophenyl sulfate. This method is not an EPA or other standardized method, and thus it has not been included in Table 7-1. 

Anderson PN, Eaton DE, Murphy SD. 1992. Comparative metabolism of methyl parathion in intact and subcellular fractions of isolated rat hepatocytes. Fundam Appl Toxicol 18 221-226. 

Benke GM, Murphy SD. 1974. The influence of age and sex on the toxicity and multiple pathways of metabolism of methyl parathion and parathion in rats. Toxicol Appl Pharmacol 29 125. 

Benke GM, Cheever KL, Mirer FE, et al. 1974. Comparative toxicity, anticholinesterase action and metabolism of methyl parathion and parathion in sunfish and mice. Toxicol Appl Pharmacol 28 97-109. 

Mirer FE, Levinl BS, Murphy SD. 1977. Parathion and methyl parathion toxicity and metabolism in piperonyl butoxide and diethyl maleate pretreated mice. Chem Biol Interactions 17 99-112. 

Radulovic LL, Laferla JJ, Kulkami AP. 1986. Human placental glutathione S-transferase-mediated metabolism of methyl parathion. Biochem pharmacol 35 3473-3480. 

Glutathione S-transferases are important in the metabolism of organophosphorus insecticides resulting in detoxification. For example, methyl parathion is dealkylated by glutathione S-transferase to form desmethyl parathion and methyl glutathione (Figure 8.21). 

Decreased sensitivity to insecticides in resistant strains of mosquitofish from Belzoni, Mississippi is partly based on their ability to metabolize the toxicant rapidly. Resistant strains converted aldrin to dieldrin and water-soluble components to a greater extent than sensitive strains89. Resistant strains also had higher activities of methyl-parathion dearylation which appear to be catalyzed by the higher levels of CYP in this strain15. 

Glutathione conjugation. The involvement of glutathione transferases in OP metabolism was realized in the early 1960 s (35. 361. It was difficult to establish this fact because of similarities between glutathione transferase-and carboxylesterase-produced metabolites. Induction of glutathione transferase activity in the fall armyworm caused a 2- to 3-fold decrease in the toxicity of diazi-non, methamidophos, and methyl parathion (37.) This shows indirectly the importance of glutathione transferase activity in the detoxification of these OPs. 

---