The role of metabolism in determining susceptibility to parathion toxicity in man

Mutch, E;, Blain, PG;, Williams, FM

doi:10.1016/S0378-4274(99)00044-2

The role of metabolism in determining susceptibility to parathion toxicity in man

Lookup NU author(s): Dr Elaine Mutch, Professor Peter Blain, Professor Faith Williams

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Abstract

Human liver microsomes (n = 16) activated parathion (O, O, diethyl O-p-nitrophenyl phosphorothioate, 20 and 200 mu M) to paraoxon at a rate of 23.3-199.3 and 18.7-310.3 pmol/min per mg protein, respectively. p-Nitrophenol, was also formed, at 321.1-769.2 and 406.2-778.3 pmol/min per mg protein. This represented a 16-fold and 2-fold range in capacity to activate and detoxify parathion, respectively. Parathion was activated with an apparent K-m of 9-16 mu M (n = 3). The activation of parathion (200 mu M) was positively correlated with nifedipine oxidation, indicating the involvement of CYP3A. Correlations were not significant with ethoxyresorufin-O-dealkylation (CYP1A1/2), pentoxyresorufin-O-dealkylation (CYP2B6), p-nitrophenol hydroxylation (CYP2E1), paraoxon hydrolysis (A-esterase) or phenylvalerate hydrolysis (B-esterase). Paraoxon formation from parathion was markedly reduced by CYP3A inhibitors. 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. This study has determined wide interindividual variations in capacity to metabolise parathion, mainly by CYP3A, which may influence its manifest toxicity.