The role of metabolism in determining susceptibility to parathion toxicityin man

Human liver microsomes (n = 16) activated parathion (O, O, diethyl O-p-nitr ophenyl phosphorothioate, 20 and 200 mu M) to paraoxon at a rate of 23.3-19 9.3 and 18.7-310.3 pmol/min per mg protein, respectively. p-Nitrophenol, wa s 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 detoxif y 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 co rrelated with nifedipine oxidation, indicating the involvement of CYP3A. Co rrelations 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 functio nally important at low levels of paraoxon. Human P450s 3A4 and 3A5 expresse d microsomes were the most efficient at biotransforming parathion to paraox on, although P450s 1A1, 2B6 and 2C8 also catalysed the reaction. This study has determined wide interindividual variations in capacity to metabolise p arathion, mainly by CYP3A, which may influence its manifest toxicity. (C) 1 999 Elsevier Science Ireland Ltd. All rights reserved.