Xu Ximing, Mathieu Cécile, Berthelet Jérémy, Duval Romain, Bui Linh Chi, Busi Florent, Dupret Jean-Marie, Rodrigues-Lima Fernando
Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, Paris, France (X.X., C.M., J.B., R.D., L.C.B., F.B., J.-M.D., F.R.L.); and Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China (X.X.).
Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, Paris, France (X.X., C.M., J.B., R.D., L.C.B., F.B., J.-M.D., F.R.L.); and Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China (X.X.)
Mol Pharmacol. 2017 Sep;92(3):358-365. doi: 10.1124/mol.117.108662. Epub 2017 Jul 3.
Thiram (tetramethylthiuram disulfide) is a representative dithiocarbamate (DTC) pesticide used in both the field and as a seed protectant. The widespread use of Thiram and other DTC pesticides has raised concerns for health, because these compounds can exert neuropathic, endocrine disruptive, and carcinogenic effects. These toxic effects are thought to rely, at least in part, on the reaction of Thiram (and certain of its metabolites) with cellular protein thiols with subsequent loss of protein function. So far, a limited number of molecular targets of Thiram have been reported, including few enzymes such as dopamine -hydroxylase, 11-hydroxysteroid dehydrogenase, and brain glycogen phosphorylase. We provide evidence that Thiram is an inhibitor ( = 23 M; = 0.085 second; / = 3691 M⋅s) of human arylamine -acetyltransferase 1 (NAT1), a phase II xenobiotic-metabolizing enzyme that plays a key role in the biotransformation of aromatic amine xenobiotics. Thiram was found to act as an irreversible inhibitor through the modification of NAT1 catalytic cysteine residue as also reported for other enzymes targeted by this pesticide. We also showed using purified NAT1 and human keratinocytes that Thiram impaired the -acetylation of 3,4-dichloroaniline (3,4-DCA), a major toxic metabolite of aromatic amine pesticides (such as Diuron or Propanil). As coexposure to different classes of pesticides is common, our data suggest that pharmacokinetic drug-drug interactions between DTC pesticides such as Thiram and aromatic amine pesticides may occur through alteration of NAT1 enzymes functions.
福美双（二硫化四甲基秋兰姆）是一种具有代表性的二硫代氨基甲酸盐（DTC）类农药，用于田间及作为种子保护剂。福美双和其他DTC类农药的广泛使用引发了对健康的担忧，因为这些化合物可产生神经病变、内分泌干扰和致癌作用。这些毒性作用被认为至少部分依赖于福美双（及其某些代谢物）与细胞蛋白硫醇的反应，随后导致蛋白质功能丧失。到目前为止，已报道的福美双的分子靶点数量有限，包括少数几种酶，如多巴胺-β-羟化酶、11-羟基类固醇脱氢酶和脑糖原磷酸化酶。我们提供的证据表明，福美双是人类芳基胺-N-乙酰基转移酶1（NAT1）的抑制剂（K i = 23 μM；k inact = 0.085秒；k inact /K i = 3691 μM·s），NAT1是一种II相异源生物代谢酶，在芳香胺类异源生物的生物转化中起关键作用。正如针对该农药靶向的其他酶所报道的那样，发现福美双通过修饰NAT1催化半胱氨酸残基而作为不可逆抑制剂起作用。我们还使用纯化的NAT1和人角质形成细胞表明，福美双损害了3,4-二氯苯胺（3,4-DCA）的N-乙酰化，3,4-DCA是芳香胺类农药（如敌草隆或敌稗）的主要有毒代谢物。由于同时接触不同种类的农药很常见，我们的数据表明，福美双等DTC类农药与芳香胺类农药之间的药代动力学药物-药物相互作用可能通过改变NAT1酶的功能而发生。
