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

被引:61
作者
Mutch, E [1 ]
Blain, PG [1 ]
Williams, FM [1 ]
机构
[1] Univ Newcastle Upon Tyne, Sch Med, Dept Environm & Occupat Med, Toxicol Unit, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
关键词
phosphorothioate pesticides; parathion; interindividual variations; acute toxicity; acetylcholinesterase; CYP3A;
D O I
10.1016/S0378-4274(99)00044-2
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:177 / 187
页数:11
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