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Title: The role of metabolism in determining susceptibility to parathion toxicity
Author: Mutch, Elaine
ISNI:       0000 0001 3437 6848
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 1998
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Phosphorothioate insecticides such as parathion (0,0, diethyl O-pnitrophenyl phosphorothioate) must undergo metabolic activation to form oxygen analogs in order to exert their toxicity. The specific isoforms of cytochrome P450 involved in this oxidative desulphuration reaction were examined in rat liver microsomes and a panel of sixteen human liver microsomes. In the rat, parathion (20μM and 200μM) was activated to paraoxon with an apparent Km of 10.4±0.25μM (n=3), the metabolic rates were 241±17 and 256±18 pmol/min/mg protein, respectively. p-Nitrophenol was also formed, at 235±15 and 220±23 pmol/min/mg protein. Human liver microsomes activated parathion (20μM and 200μM) with an apparent Km of 9μM-16μM (n=3), the metabolic rates were 23.3-199.3 and 18.7-310.3 pmol/min/mg protein (n=16). p-Nitrophenol was also formed, at 321.1- 769.2 and 406.2-778.3 pmol/min/mg protein. The activation of parathion (200μM) by human liver microsomes was positively correlated with nifedipine oxidation, indicating the involvement of CYP3A. Correlations were not significant with ethoxyresorufin-0-dealkylation, pentoxyresorufin-0-dealkylation, pnitrophenol hydroxylation, paraoxon hydrolysis or phenylvalerate hydrolysis. Paraoxon formation from parathion by human liver microsomes was markedly inhibited by the CYP3A inhibitors ketoconazole, quercetin and naringenin (apparent Ki=21μM). Metyrapone and a-naphthflavone had some inhibitory effect. The inhibitors were generally less effective towards parathion metabolism by rat liver microsomes. Experiments with EDTA indicated that A-esterase was not functionally important at low levels of paraoxon. Human P450s 3A4 and 3A5 expressed microsomes were the most efficient at biotransforming parathion to paraoxon, although P450s 1A1,2B6 and 2C8 also catalysed the reaction. The present study has shown marked interindividual variation in the metabolism of parathion, which may influence toxicity following exposure to this or other phosphorothioates. Co-administration of inhibitors or inducers of the enzymes involved may affect the fate of parathion and thus enhance or reduce its toxicity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organophosphate pesticides