Uptake, clearance, and metabolism of parathion by perfused whole pig livers

Baker, S R; McGilliard, A.D.; Dahm, Paul A.

doi:10.1016/0048-3575(79)90044-0

Cited by 9 publications

(3 citation statements)

References 29 publications

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“…The increased formation of paraoxon from parathion by pretreatment with dexamethasone was supported by enzyme kinetic studies using hepatic microsomal fractions; in DXT rats, the K m , V max , and Cl int were significantly faster (or higher) than those in DXT rats ( Table 3). Parathion is a high hepatic extraction compound; the hepatic extraction ratios were 82-97% in dogs [35], and approximately 80% [36] and 68.7 -97.8% [1] for rat and pig isolated perfused liver, respectively, hence the Cl value of parathion was considerably high (Table 1). Therefore, the Cl of parathion could be affected by hepatic blood flow and hepatic intrinsic clearance [37].…”

Section: Discussionmentioning

confidence: 99%

“…Parathion is one of the toxic organophosphorus insecticides and was usually used for agricultural purposes. In animals, biotransformation of parathion involves a deactivating pathway to form diethylphosphorothioate and p-nitrophenol, and an activating pathway to form paraoxon through cytochrome P450-dependent oxidative desulfuration followed by a deactivating pathway to form diethylphosphate and pnitrophenol by hydrolysis [1,2]. The acute mam-malian toxicity of parathion results from paraoxon which is a potent and irreversible inhibitor of acetylcholinesterase.…”

Section: Introductionmentioning

confidence: 99%

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

Hurh¹,

Lee²,

Lee³

et al. 2000

Biopharm. Drug Dispos.

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hurh¹,

Lee²,

Lee³

et al. 2000

Biopharm. Drug Dispos.

View full text Add to dashboard Cite

show abstract

“…In animals, biotransformation of parathion involves a deactivating pathway to form diethylphosphorothioate and p-nitrophenol, and an activating pathway to form paraoxon through hepatic cytochrome P450 (CYP)-dependent oxidative desulphuration followed by a deactivating pathway to form diethylphosphate and p-nitrophenol by hydrolysis [1,2]. The acute mammalian toxicity of parathion results from paraoxon, a potent and irreversible inhibitor of acetylcholinesterase.…”

Section: Introductionmentioning

confidence: 99%

Effects of physostigmine on the pharmacokinetics of intravenous parathion in rats

Hurh

Lee

Kim

et al. 2000

Biopharm & Drug Disp

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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.

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Organophosphorus insecticides

Hassall¹

1990

The Biochemistry and Uses of Pesticides

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Uptake, clearance, and metabolism of parathion by perfused whole pig livers

Cited by 9 publications

References 29 publications

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

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

Effects of physostigmine on the pharmacokinetics of intravenous parathion in rats

Organophosphorus insecticides

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