Toxicology Letters 107 (1999) 177 – 187 The role of metabolism in determining susceptibility to parathion toxicity in man Elaine Mutch *, Peter G. Blain, Faith M. Williams The Toxicology Unit, Deptartment of Enironmental and Occupational Medicine, The Medical School, Newcastle Uniersity, NE24HH, UK Accepted 31 January 1999 Abstract Human liver microsomes (n =16) activated parathion (O, O, diethyl O-p -nitrophenyl phosphorothioate, 20 and 200 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 M (n =3). The activation of parathion (200 M) was positively correlated with nifedipine oxidation, indicating the involvement of CYP3A. Correlations were not significant with ethoxyresorufin-O-dealkylation (CYP1A1/2), pen- toxyresorufin-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. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Phosphorothioate pesticides; Parathion; Interindividual variations; Acute toxicity; Acetylcholinesterase; CYP3A 1. Introduction Phosphorothioate insecticides are used widely in agriculture and public health. They are, how- ever, potentially toxic to man because of their capacity to inhibit acetylcholinesterase (EC 3.1.1.7) at nerve synapses and at the neuro–mus- cular junction. The parent phosphorothioates are weak acetylcholinesterase inhibitors but are toxic following activation by desulphuration to the oxy- gen analogue (oxon) which is a potent anti- cholinesterase (Gallo and Lawryk, 1991). They are metabolised by a number of activation and detoxification reactions proceeding concurrently and sequentially which occur mainly in liver but also in extrahepatic tissues. The balance between * Corresponding author. Tel.: +44-191-2227015; fax: +44- 191-2226442. E-mail address: elaine.mutch@ncl.ac.uk (E. Mutch) 0378-4274/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII:S0378-4274(99)00044-2