Foetal and adult human CYP3A isoforms in the bioactivation of organophosphorothionate insecticides
Foetal and adult human CYP3A isoforms in the bioactivation of organophosphorothionate insecticides
复制标题
DOI：
10.1016/j.toxlet.2006.10.006
复制
发表时间：
2006-12-15
影响因子：
3.5
通讯作者：
Testai, Emanuela
中科院分区：
文献类型：
--
作者：
Buratti, Franca M.;Leoni, Claudia;Testai, Emanuela
在人类中，已证实产前接触有机硫代磷农药（OPT）。由于OPT-induced neurodevelopmental effects may be due to in situ bioactivation by fetal enzymes，the catalytic activity of fetal CYP3A7 to chlorpyrifos（CPF），degradion（PAR），malathion（MAL）and fethion（FEN）has been assessed by using recombinant enzymes.还与成人亚型CYP 3A 4和CYP 3A 5进行了比较。在检测浓度范围（0.05-200 μ M）内，CYP 3A 7能够从4种OPTs中产生显著水平的oxon或亚砜。当比较CYP 3A亚型的效率时，以CLi值表示的排序为：CPF = 3A 4> 3A 5> 3A 7; PAR = 3A 4>> 3A 7>> 3A 5; MAL = 3A 4> 3A 7> 3A 5; FEN（亚砜形成）= 3A 4> 3A 5>> 3A 7。CYP 3A 5的活性对单一杀虫剂的依赖性大于其同工酶CYP 3A 4。结果表明，CPF、MAL和PAR的CYP 3A 7在体内形成的毒性代谢物对乙酰胆碱酯酶有抑制作用，而FEN则无此作用。然而，由于胎肝重量较小，对总OPT生物转化的贡献相对较低。另一方面，我们的结果清楚地表明，在低CPF浓度下，胎儿中无毒代谢产物的形成非常有利。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
In humans organophosphorothionate pesticides (OPT) prenatal exposure has been demonstrated. Since OPT-induced neurodevelopmental effects may be due to in situ bioactivation by foetal enzymes, the catalytic activity of the foetal CYP3A7 toward chlorpyrifos (CPF), parathion (PAR), malathion (MAL) and fenthion (FEN) has been assessed by using recombinant enzymes. A comparison with the adult isoforms CYP3A4 and CYP3A5 has been also carried out. CYP3A7 was able to produce significant levels of oxon or sulfoxide from the four OPTs in the range of tested concentrations (0.05-200 mu M). When the efficiencies of CYP3A isoforms were compared, the ranking, expressed as CLi values, were: CPF = 3A4 > 3A5 > 3A7; PAR = 3A4 >> 3A7 >> 3A5; MAL = 3A4 > 3A7 > 3A5; FEN (sulfoxide formation) = 3A4 > 3A5 >> 3A7. The CYP3A5 efficiency appeared to be more dependent on the single insecticide than its related isozyme CYP3A4.Our results indicate that the levels of toxic metabolite formed in situ by CYP3A7 from CPF, MAL and PAR but not from FEN have the chance to inhibit acetylcholinesterase, following prenatal exposure to OPTs. However, due to the smaller weight of foetal liver, the contribution to total OPT biotransformation is relatively low. On the other hand, our results clearly indicate that at low CPF concentrations, the formation of the non-toxic metabolites is highly favoured in the foetus. (c) 2006 Elsevier Ireland Ltd. All rights reserved.