Ford Kevin A, Casida John E
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Chem Res Toxicol. 2006 Nov;19(11):1549-56. doi: 10.1021/tx0601859.
The established neonicotinoid insecticides have chloropyridylmethyl (imidacloprid, thiacloprid, acetamiprid, and nitenpyram), chlorothiazolylmethyl (thiamethoxam or TMX and clothianidin or CLO) or tetrahydrofuranylmethyl (dinotefuran or DIN) substituents. We recently reported the metabolic fate of the chloropyridylmethyl neonicotinoids in mice as the first half of a comparative study that now considers the chlorothiazolylmethyl and tetrahydrofuranylmethyl analogues. TMX, CLO, two desmethyl derivatives (TMX-dm and CLO-dm), and DIN were administered ip to mice at 20 mg/kg for characterization of metabolites and pharmacokinetic analysis of brain, liver, plasma, and urine by HPLC/DAD and LC/MSD. Each compound is excreted 19-55% unmetabolized in urine within 24 h, and tissue residues are largely dissipated by 4 h. Thirty-seven metabolites of TMX, TMX-dm, CLO, and CLO-dm are identified by comparison with synthetic standards or their structures are proposed by molecular weights and 35Cl:37Cl ratios often supplemented by previous reports or sequence studies in which intermediates are readministered. A facile reaction sequence involves TMX --> TMX-dm or CLO --> CLO-dm. CLO-dm, reported to be a contributor to TMX hepatocarcinogenesis in mice, is unexpectedly remethylated in part to CLO in brain. The nitrosoguanidine, aminoguanidine, and urea derivatives of the parent compounds are detected in the tissues and methylnitroguanidine, methylguanidine, and nitroguanidine in the urine. Chlorothiazolecarboxaldehyde from oxidative cleavage of TMX and CLO is quite persistent in brain, liver, and particularly plasma compared with chloropyridinecarboxaldehyde and tetrahydrofurancarboxaldehyde from the other neonicotinoids. Chlorothiazolecarboxylic acid is conjugated with glycine or glucuronic acid or converted to S-methyl and mercapturate derivatives. DIN metabolism involves nitro reduction, N-demethylation, N-methylene hydroxylation, and amine cleavage, and tetrahydrofuranylmethyl hydroxylation at the 2-, 4-, and 5-positions giving 29 tentatively identified metabolites. The diversity of biodegradable sites and multiple pathways insures against parent compound accumulation but provides intermediates reported to be active as nicotinic agonists and inducible nitric oxide synthase inhibitors.
已确立的新烟碱类杀虫剂含有氯吡啶甲基（吡虫啉、噻虫啉、啶虫脒和烯啶虫胺）、氯噻唑甲基（噻虫嗪或TMX和噻虫胺或CLO）或四氢呋喃甲基（呋虫胺或DIN）取代基。我们最近报道了氯吡啶甲基新烟碱类化合物在小鼠体内的代谢命运，这是一项比较研究的前半部分，现在该研究考虑了氯噻唑甲基和四氢呋喃甲基类似物。将TMX、CLO、两种去甲基衍生物（TMX-dm和CLO-dm）以及DIN以20mg/kg的剂量腹腔注射给小鼠，通过HPLC/DAD和LC/MSD对脑、肝、血浆和尿液中的代谢物进行表征和药代动力学分析。每种化合物在24小时内有19 - 55%以未代谢形式经尿液排出，组织残留大部分在4小时内消散。通过与合成标准品比较鉴定出TMX、TMX-dm、CLO和CLO-dm的37种代谢物，或者根据分子量和35Cl:37Cl比率推测其结构，这些比率通常由先前的报告或序列研究补充，在这些研究中会再次给予中间体。一个简单的反应序列是TMX→TMX-dm或CLO→CLO-dm。据报道，CLO-dm是小鼠TMX肝癌发生的一个促成因素，但在脑中它意外地部分重新甲基化形成CLO。在组织中检测到母体化合物的亚硝基胍、氨基胍和尿素衍生物，在尿液中检测到甲基硝基胍、甲基胍和硝基胍。与其他新烟碱类化合物产生的氯吡啶甲醛和四氢呋喃甲醛相比，TMX和CLO氧化裂解产生的氯噻唑甲醛在脑、肝尤其是血浆中相当持久。氯噻唑羧酸与甘氨酸或葡萄糖醛酸结合，或转化为S-甲基和硫醚氨酸衍生物。DIN的代谢涉及硝基还原、N-去甲基化、N-亚甲基羟基化和胺裂解，以及在2-、4-和5-位的四氢呋喃甲基羟基化，产生29种初步鉴定的代谢物。可生物降解位点的多样性和多种途径可确保母体化合物不会积累，但会产生据报道具有烟碱激动剂和诱导型一氧化氮合酶抑制剂活性的中间体。
