Bioactivation of Substituted Thiophenes Including α-Chlorothiophene-Containing Compounds in Human Liver Microsomes
Bioactivation of Substituted Thiophenes Including α-Chlorothiophene-Containing Compounds in Human Liver Microsomes
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DOI：
10.1021/tx100386z
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发表时间：
2011-05-01
影响因子：
4.1
通讯作者：
Gan, Jinping
中科院分区：
文献类型：
--
作者：
Chen, Weiqi;Caceres-Cortes, Janet;Gan, Jinping
噻吩部分已被认为是一个毒基，因为潜在的氧化生物活化导致亲电物种。在硫原子的α-碳上引入大体积或吸电子基团具有减少或消除生物活化的潜力。在这篇文章中，我们描述了各种取代噻吩的生物活性。将这些化合物在添加或不添加还原型谷胱甘肽（GSH）作为捕获剂的NADPH强化人肝微粒体中孵育。所得的GSH加合物，其特征在于通过高效液相色谱/高分辨率质谱与背景扣除法的援助。在检测的5种α-氯噻吩中，有4种形成了NADPH依赖性GSH加合物。大多数加合物的质量与GSH对氯的名义取代一致。1-（5-氯噻吩-2-基）乙酮（1a）的主要GSH加合物的LC/MS/MS和质子NMR证实GSH置换了氯。为了进一步探索不同取代对生物活化潜力的影响，在使用丹酰谷胱甘肽的定量巯基捕获测定中测试了一系列在C4或CS位置取代的2-乙酰基噻吩。在C4或C5位置的取代得到加合物水平，其以以下顺序降低：4-H，5-H（无取代）> 4-Br，类似于4-Cl > 5-Cl > 5-CN > 4-CH（3）> 5-Br > 5-CH（3）（未检测到加合物）。总之，在一系列取代的噻吩中检测到了生物活性。虽然噻吩环上的取代可以减少反应性代谢物的形成，但减少的程度取决于取代位置和取代基。
The thiophene moiety has been recognized as a toxicophore because of the potential of oxidative bioactivation leading to electrophilic species. The introduction of bulky or electron-withdrawing groups at the alpha-carbon to the sulfur atom has the potential to reduce or eliminate bioactivation. In this article, we describe the bioactivation of a variety of substituted thiophenes. These compounds were incubated in NADPH-fortified human liver micro somes with or without the addition of reduced glutathione (GSH) as a trapping agent. The resulting GSH adducts were characterized by high performance liquid chromatography/high resolution mass spectrometry with the aid of a background subtraction methodology. Four of the five alpha-chlorothiophenes tested formed NADPH-dependent GSH adducts. Most adducts had masses consistent with the nominal substitution of chlorine by GSH. LC/MS/MS and proton NMR of the major GSH adduct of 1-(5-chlorothiophen-2-yl)ethanone (1a) confirmed that GSH displaced chlorine. To further explore the effect of different substitutions on the bioactivation potential, a series of 2-acetylthiophenes substituted at the C4 or CS positions were tested in a quantitative thiol-trapping assay using dansyl glutathione. Substitutions at the C4 or C5 positions gave adduct levels that decreased in the following order: 4-H, 5-H (no substitution) > 4-Br similar to 4-Cl > 5-Cl > 5-CN > 4-CH(3) > 5-Br > 5-CH(3) (no adduct detected). In conclusion, bioactivation was detected in a series of substituted thiophenes. Although substitutions on the thiophene ring can reduce the formation of reactive metabolites, the degree of reduction is dependent on the substitution position and substituent.